CA2158457C - Naphthalene derivatives - Google Patents
Naphthalene derivatives Download PDFInfo
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- CA2158457C CA2158457C CA002158457A CA2158457A CA2158457C CA 2158457 C CA2158457 C CA 2158457C CA 002158457 A CA002158457 A CA 002158457A CA 2158457 A CA2158457 A CA 2158457A CA 2158457 C CA2158457 C CA 2158457C
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- naphthalene
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- alkyl
- ethyl acetate
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract
Compounds of formula (I) where R1 is of formulae (II), (III), or (IV), or (V); R2 is -R4, -O-R4, -O-S(O)2-R4, -NR4R5, R4-(CH2)b-NH(C-X)- (CH2)c-, R4-(CH2)b-O(C-O)NH-(CH2)c-(C=O)NH- R4-(C=O)NH-(C=O)NH-, -(CH2)b-NH(C= X)- (CH2)c-R4, R4-(CH2)b-O(C=O)-(CH2)c-, -(CH2)b-O(C-O)-(CH2)c-R4, -NH(C=X)NH-R4, R4-O(C-O)O-, -O(C-O)NH-R4, R4-O(C-O)NH-, -(CH2)b-(C-O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5, -CH(OH)-R4, -(C-O)-NR4R5, -CN, -NO2, substituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkenyl, or substituted or unsubstituted C1 to C6 alkynyl, said substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4, or-S(O)d-R4; R3 is hydrogen, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl; R4 and R5 are each independently (XV), (XVI), (XVII), hydrogen, -CF3, C1 to C6 alkyl, C1 to C6 alkylaryl, with the proviso that when R2 is -R4 or -OR4, R4 is not hydrogen or C1 to C6 alkyl. These comrounds are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and antagonists and may be used in the treatment of depression, anxiety, eating disorders, o besity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicranla and headache associated with vascular disorder s, and other disorders arising from deficient serotonerg ic neyritransmission. The compoundscan also be used as centrally acting antihyp ertensives vasodilators.
Description
NAPHTHALENE DERIVATIVES
Background of the Invention The present invention relates to naphthalene derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are selective agonists and antagonists of serotonin 1 (5-HT1) receptors and as such are useful in treating migraine and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 43,4561-A describes 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are claimed to be 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain. However, EP 434,561-A neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
European Patent Publication 343,050-Al describes 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as 5-HTlAligands useful in therapy. However, EP 343,050-A1 neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
Drug Res. Dev., 1991,22,25 describes 7-methoxy-1-(1-piperazinyl)-naphthalene as a 5-HT1 ligand. This publication neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the y s present invention.
Thus ligands with high affinity for the 5-HT1, receptors are well recognized as having therapeutic value for the treatment of human conditions caused by serotonin imbalance.
Summnary of the Invention The present invention relates to compounds of the formula:
R2 \ \
I
/ /
(where R1 is a group of the formula:
R3 Rs ~a N N
N N-R3 , N-R3 , ~ > or ;
~ ~a II III IV V
R2 is -R4-, -O-R4-, -O-S(O)2-R4-, -NR4R6.
-(CH2)c-(C=X)NH-(CH2)b-R4, -NH(C=O)-(CH2)c-NH(C=O)O-(CH2)b-R4, -NH(C=O)-NH(C=O)-R4, -(CH2)b-NH(C=X)-(CH2)c-R4, -(CH2)c-(C=O)O-(CH2)b-R4, -(CH2)b-O(C=O)-(CH2)c-R4, -NH(C=X)NH-R4, -O(C=O)O-R4, -O(C=O)NH-R4, -NH(C=O)O-R4, -(CH2)b-(C=O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5, -CH(OH)-R4, -(C=O)-NR4R5, -CN, -N02, substituted C1 to C6 alkyl, substituted or unsubstituted C2 to C6 alkenyl, or substituted or unsubstituted C2 to C6 alkynyl, the substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4 or -S(O)d-R4;
R3 is hydrogen, CH30CH2CH2, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl;
R4 and R5 are each independently R6 ~R is N _____M
R~~B~A
Rl~i-GR11 Ris ~ N~
D~ F~ R -J O L-R8 E Rlo i3 Wig' R ~ ~R
i6 is R9 Ria Rm XV XVI XVII
hydrogen, -CF3, C1 to C6 alkyl, Cl to C6 alkylaryl, with the proviso that when R2 is -R4 or -OR4, R4 is not hydrogen or Cl to C6 alkyl;
R6. R7. RS. R9. R10. R11. R12. R13. R14. R15. R16. R17.
and R18 are each independently H, halogen, -CF3, -(C=O)R20, -CN, -OR20~ -~20R21~ -~20S02R22~ -N=C=N(~3)2~ -N20C02R22~
-S(O)eR20, -S02NR20R21~ -N02~ az'Yl, C1 to C6 alkylaryl, -(C=O)OR20, -(C=O)NR20R21, Cl to C6 alkyl, C2 to C6 alkenyl, and C2 to C6 alkynyl;
R6 and R~, R~ and R8, R8 and R9, R9 and R10, R11 and R12. R12 and R13, R13 aad R14, R15 and R16, R16 and R1~.. and R1~ and Rlg may be taken together to form a five-to seven-membered alkyl ring, a six-membered aryl ring, a five-to v - 3a - 215 8 4 5 7 seven-membered heteroalkyl ring having one heteroatom of N, O, or S, or a five-to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S;
M is C, N, C=O or C-O;
R19 is hydrogen or C1 to C3 alkyl when M is C, N or C-O
and R19 is absent when M is C=O;
R20 and R21 are each independently hydrogen, Cl to C6 alkyl, aryl, or C1 to C6 alkylaryl, or may be taken together to form a C4 to C7 alkyl ring;
R22 is Cl to C6 alkyl, aryl, or C1 to C6 alkylaryl;
A, B, D, E and F are each independently C or N;
G, I, J, and K are each independently C, N, O, S, or (C=O), with the proviso that there is at most one of O, (C=O), or S per ring;
L and Z are each independently C or N;
X is O or S;
a is 0, 1 or 2;
a is 0, 1 or 2;
d is 0, 1, or 2;
b and c are each independently 0, 1, 2, 3, 4, 5, or 6, with b+c being at most 6;
a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein the substituted phenyl is substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C1 to C4 alkoxy), -~ 64680-827 - 3b -and pharmaceutically acceptable salts thereof.
The compounds of the invention include all optical isomers of formula I (e. g. R and S enantiomers) and their racemic and diastereomeric mixtures. When Rl is - ...
Background of the Invention The present invention relates to naphthalene derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are selective agonists and antagonists of serotonin 1 (5-HT1) receptors and as such are useful in treating migraine and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 43,4561-A describes 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are claimed to be 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain. However, EP 434,561-A neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
European Patent Publication 343,050-Al describes 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as 5-HTlAligands useful in therapy. However, EP 343,050-A1 neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the present invention.
Drug Res. Dev., 1991,22,25 describes 7-methoxy-1-(1-piperazinyl)-naphthalene as a 5-HT1 ligand. This publication neither discloses nor suggests the type of 7-substituted 1-(1-piperazinyl)-naphthalenes provided by the y s present invention.
Thus ligands with high affinity for the 5-HT1, receptors are well recognized as having therapeutic value for the treatment of human conditions caused by serotonin imbalance.
Summnary of the Invention The present invention relates to compounds of the formula:
R2 \ \
I
/ /
(where R1 is a group of the formula:
R3 Rs ~a N N
N N-R3 , N-R3 , ~ > or ;
~ ~a II III IV V
R2 is -R4-, -O-R4-, -O-S(O)2-R4-, -NR4R6.
-(CH2)c-(C=X)NH-(CH2)b-R4, -NH(C=O)-(CH2)c-NH(C=O)O-(CH2)b-R4, -NH(C=O)-NH(C=O)-R4, -(CH2)b-NH(C=X)-(CH2)c-R4, -(CH2)c-(C=O)O-(CH2)b-R4, -(CH2)b-O(C=O)-(CH2)c-R4, -NH(C=X)NH-R4, -O(C=O)O-R4, -O(C=O)NH-R4, -NH(C=O)O-R4, -(CH2)b-(C=O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5, -CH(OH)-R4, -(C=O)-NR4R5, -CN, -N02, substituted C1 to C6 alkyl, substituted or unsubstituted C2 to C6 alkenyl, or substituted or unsubstituted C2 to C6 alkynyl, the substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4 or -S(O)d-R4;
R3 is hydrogen, CH30CH2CH2, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl;
R4 and R5 are each independently R6 ~R is N _____M
R~~B~A
Rl~i-GR11 Ris ~ N~
D~ F~ R -J O L-R8 E Rlo i3 Wig' R ~ ~R
i6 is R9 Ria Rm XV XVI XVII
hydrogen, -CF3, C1 to C6 alkyl, Cl to C6 alkylaryl, with the proviso that when R2 is -R4 or -OR4, R4 is not hydrogen or Cl to C6 alkyl;
R6. R7. RS. R9. R10. R11. R12. R13. R14. R15. R16. R17.
and R18 are each independently H, halogen, -CF3, -(C=O)R20, -CN, -OR20~ -~20R21~ -~20S02R22~ -N=C=N(~3)2~ -N20C02R22~
-S(O)eR20, -S02NR20R21~ -N02~ az'Yl, C1 to C6 alkylaryl, -(C=O)OR20, -(C=O)NR20R21, Cl to C6 alkyl, C2 to C6 alkenyl, and C2 to C6 alkynyl;
R6 and R~, R~ and R8, R8 and R9, R9 and R10, R11 and R12. R12 and R13, R13 aad R14, R15 and R16, R16 and R1~.. and R1~ and Rlg may be taken together to form a five-to seven-membered alkyl ring, a six-membered aryl ring, a five-to v - 3a - 215 8 4 5 7 seven-membered heteroalkyl ring having one heteroatom of N, O, or S, or a five-to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S;
M is C, N, C=O or C-O;
R19 is hydrogen or C1 to C3 alkyl when M is C, N or C-O
and R19 is absent when M is C=O;
R20 and R21 are each independently hydrogen, Cl to C6 alkyl, aryl, or C1 to C6 alkylaryl, or may be taken together to form a C4 to C7 alkyl ring;
R22 is Cl to C6 alkyl, aryl, or C1 to C6 alkylaryl;
A, B, D, E and F are each independently C or N;
G, I, J, and K are each independently C, N, O, S, or (C=O), with the proviso that there is at most one of O, (C=O), or S per ring;
L and Z are each independently C or N;
X is O or S;
a is 0, 1 or 2;
a is 0, 1 or 2;
d is 0, 1, or 2;
b and c are each independently 0, 1, 2, 3, 4, 5, or 6, with b+c being at most 6;
a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein the substituted phenyl is substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C1 to C4 alkoxy), -~ 64680-827 - 3b -and pharmaceutically acceptable salts thereof.
The compounds of the invention include all optical isomers of formula I (e. g. R and S enantiomers) and their racemic and diastereomeric mixtures. When Rl is - ...
H N
~a the R enantiomers at the chiral carbon designated by an asterisk in formula I
are preferred.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to hereih (e.g. alkoxy), may be linear or branched, and they may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
The following compounds are preferred:
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzamido-1-(1-piperazinyl)-naphthalene;
7-Acetamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxycarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Nitro-2-pyridinylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Hydroxy-3-methyl-1-butynyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(2-Ethylsulfonyl)ethenyl-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Methylaminosulfonylphenyl)-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methylsulfonylaminophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Fluorophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzoyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Imidazolo[4,5-b)pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ ~ PCT/US94/01206 7-(Benzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Cyanobenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(1,2,3-Triazolo[4,5-b)pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Trifluoromethylbenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(6,7-Dichlorobenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxymethyl]quinoline;
1-Methyl-4-~7-[2-(4-chlorophenyl)thiazol~-ylmethoxy)naphthalen-1-yl}piperazine;
1-Methyl-4-[7-(5-chloro-thiophen-2-ylmethoxy)napthalen-1-yl)piperazine;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid phenylamide;
7-Amino-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(Imidazolo [4,5-b]pyridin-1-yl)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido-1-( 1-methyl-4-piperidinyl)-naphthalene;
7-Amino-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(Imidazolo[4,5-b)pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-Benzamido-1-( 1-methyl-3-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-propyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-ethyl-1-piperazinyl)-naphthalene;
7-Amino-1-( 1-methyl-3-pyrrolidinyl)-naphthalene;
7-Benzamido-1-(1-methyl-3-pyrrolidinyl)-naphthalene;
7-Formamido-1-(pyrrolidin-2-(R)-ylmethyl)-naphthalene hydrochloride;
7-Amino-1-( 1-piperazinyl)-naphthalene;
7-(Imidazolo-[4,5-b)-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene; and 7-(1,2,3-Triazolo-[4,5-b)-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene;
The following compounds are particularly preferred:
7-(Imidazolo [4,5-b) pyridin-1-yl)-1-(I-methylpyrrolidin-3-yl)naphthalene;
7-(4-Chlorobenzamido)-1-(pyrrolidin-2-(R)-ylmethyl)naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxy)nicotinonitrile;
1-(4-Methylpiperazin-1-yl)-7-pyrimidin-5-yl)naphthalene;
7-(5-Cyanopyridin-3-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
1-(Piperazin-1-yl)-7-(pyrimidin-5-yl)naphthalene;
SUBSTITUTE SHEET (RULE 26) ~ ~ ~~r~
'~ -s-7-(4-Chlorobenzamido-1-(4-methylpiperazin-1-yl)naphthalene;
7-(3-Methoxyphenyl) 1-(4-methyipiperazin-1-yl)naphthalene;
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide;
7-Pyrimidin-2-yloxy-1-(4-methylpiperazin-t-yl)naphthalene;
7-(4-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)-naphthalene;
7-(Benzimidazol-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene; and &(1-Methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide.
Other compounds believed to be most preferred are the following:
~p 1-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-4-methyl-piperazine;
4-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-1-methyl-piperidine;
7-(3-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene; and 7-(4-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene.
The present invention also relates to a pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, Alzheimers disease, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carver.
The present invention also relates to a method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, Alzheimers disease, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ 1 ~ ~ ~ ~ 7 PCT/US94/01206 _7_ (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a method for treating disorders arising firom deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a compound of the fom~ula R Ri \ \
I
/ /
where R, is of the formulae -N N-R3, N-R3, or R3 ~R3 N N
or ~a IV V
Rz is (Methyl),Sn- or (Butyl)3Sn-; R, is hydrogen , C, to Ce alkyl, C, to Cs alkylaryl, or aryl; a is 0, 1, or 2; and a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are SUBS?ITUTE SHEET (RULE 26) y~
-7~1-independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C, to C~
alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C, to C~ alkoxy.
These compounds include all optical isomers of formula I (e.g. R and S
enantiomers) and their racemic and diastereomeric mixtures. When R, is SUBSTITUTE SHEET (RULE 26) n WO 94/21619 . "' PCT/US94/01206 ~1~8~~~
H N
~a the R enantiomers at the chiral carbon designated by an asterisk in formula I
are preferred. These compounds are useful as intermediates in preparing compounds of formula I.
Detailed Description of the Invention Compounds of formula I of this invention where R' is of the formula II are prepared by the following reaction of an o-tetralone of formula V with a suitable piperazine of formula VI.
SUBSTITUTE SHEET (RULE 26) 15 ~ ~5'~ _$ , _ w ! + H-N N-R3 i VI
,o I I
, 5 N~ N
I
NJ N
R
w w w w ~/ I I
The so called enamines of formula VII are generally prepared by this reaction in the presence of an acid catalyst such as, for example, p-toluenesuffonic acid or titanium tetrachloride. If desired, the water formed as a by-product of the reaction may be effectively removed from the reaction as it is formed by the use of a reagent such as SUBSTITUTE SHEET (RULE 26) WO 94/21619 e7 ~ PCT/US94/01206 molecular sieves or calcium sulfate, or by azeotropic removal employing a Dean Stark trap with a refluxing solvent. The reaction is typically run in n reaction inert solvent such as benzene, toluene, tetrahydrofuran, or methylene chloride, at a temperature of from about -78°C to about 150°C. When titanium tetrachloride is used as the acid catalyst, the preferred temperature for the reaction is from about -78°C to about 25°C.
When azeotropic water separation is employed, the preferred reaction temperature is the boiling temperature of the particular reaction solvent.
In general, the a tetralones of formula V, for example, where Rz is -OH, -NOz, or -NHZ are known in the literature and can be readily prepared by those skilled in the art, such as, for example 7-amino-a-tetralone, (J. Med. Chem., 1976, 19, 472) and 7 hydroxy-a-tetralone, (Tetrahedron Lett., 1981, 22, 603). Other a tetralones of formula V are readily prepared using the alkylation, acylation, and organometallic reactions described herein and in standard synthesis texts, for example Organic Synthesis, wiev, New York). The piperazines of formula VI are commercially available or can be made using methods known in the art.
The enamines of formula VII may be converted to compounds of formula I by an oxidative process. The reaction may be carried out using a variety of methods known in the art. Among the acceptable oxidizing agents are noble metal catalysts, such as, palladium or platinum on activated carbon if desired, chloranil, and sulfur. The reactions can be carried out in a reaction inert solvent for example, toluene, xylene, tetrahydrofuran, methylene chloride, preferably toluene or xylene, however a solvent is not always necessary, especially for oxidations carried out with elemental sulfur. The oxidation reactions generally proceed at a temperature of about 0°C to about 250°C.
Preferred temperatures for the oxidation depend on the particular oxidant in use and are about 60°C to about 150°C for noble metal catalytic oxidation, about 150°C to about 250°C for sulfur oxidation and about 0°C to about 100°C for chloranil oxidations. From 1 to 5 equivalents, preferably 2-4 equivalents, of an additive such as dicyclopentadiene or [2,2,2) bicyclooctene may be added to the reaction to reduce the amounts of enamine reduction side products which may fomn competitively with the desired naphthalene product.
Additional compounds of formula I may also be formed using standard chemical transformations on other compounds of formula I. For example, when Rz is R,(C=O)NH- or R,(C=O)O-, these groups may be hydrolyzed in the presence of SUBSTINTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 aqueous acid or base to form -NHz and -OH groups, respectively. These standard hydrolysis reactions may be carried out in water with any of a variety of acids or bases (for example HCI, HBr, NaOH, or KOH, preferably acid for amidehydrolysis and base for ester hydrolysis) and a cosohrent (methanol or tetrahydrofuran, for example) may be used if desired to promote dissolution of I in the medium. The reaction may be carried out at a temperature of from about 0°C to about 150°C.
The preferred reaction temperature is about 20°C to about 40°C for basic hydrolysis and about the boiling temperature of the mixture for acidic hydrolysis.
Ri Ri t0 R2 w w R2 w w / / / /
R~=Ra ( C=0 > 0- , Rz=OH , NH2 R4 ( C=0 > NH-Additional compounds of formula I may be prepared by a reaction using an alkylating or acylating agent (alkyl halide, mesylate, triflate, etc., or arylalkyl halide, mesylate, triflate, etc., or an alkyl or aryl anhydride, or an alkyl or aryl carboxylic acid chloride, etc.) with compounds of formula I where Rz = -NHz or -OH. Suitable alkylating agents could include compounds of the formulae R,-(CHz)ti Y or RS-(CHz)d Y
where b is 0 to 3 and Y is a suitable leaving group, such as, for example, Br, I, or triflate. Suitable acylating agents could include acid chlorides (e.g. R;
(CH2)e (C=O)-CI
or R5-(CHz)e (C=O)-CI) or acid anhydrides (e.g. (R4 (CHz)e (C=O))z O or (R5-(CHz)d (C=O))z-O, where b is 0 to 3). The reaction may be carried out in a reaction inert solvent such as tetrahydrofuran and dichloroethane for the alkylating and acylating reactions. Preferred solvents depend on the solubility of the reagents and the selection thereof would be known to one skilled in the art. These alkylation or acylation reactions are carried out at temperatures of between about 0°C to about 200°C depending on the nature of the reaction. Preferred temperatures are between about 0 ° C to about 75°C for the acylation reactions and between about 25°C to about 100°C for the alkylation reactions.
SUBSTITUTE SHEET (RULE 26) Additional compounds of formula I may be prepared by the well known reductive alkylation reaction of the compounds of formula I where R~ is -NHS with aldehydes and ketones in the presence of hydrogen gas and a platinum or palladium catalyst or in the presence of a reducing agent such as sodium cyanoborohydride.
Other compounds of formula I can be synthesized using an activated aromatic or heterocylic compound, which are either commercially available or can be produced using methods known in the art. To form the additional compounds, these reactants are reacted with compounds of formula I where Rz is OH or NHz. As shown below, the term activated aromatic or heterocycfic compound implies a ring compound of formulae VIII or IX;
SUBSTITUTE SHEET (RULE 26) ~~1~~ ~~J
-11~1-i R~ Y
R 2 w w ~ B~
+ n Re O~E~F~Rio I
I VIII
R2=OH, NHz R6 Ri R'~8~~ w w n RB/O~E~F\Rio ~ i I
1 0=0 , NH
R~12 ~Rl + _ / / Ri3 ~~ ~L Y
K
I
Ria Ix R2=OH, NH2 R~12 ,R11 ID\ _ R ~ 3 ~'~K~~ G
I
Rya 1 Q=0 , NH
SUBSTITIfff SHEET (RULE 26) ~15'~4~~
_, , ~2_ where Y is a suitable leaving group (for example halogen or trifluoromethanesulfonyloxy) and the ring is rendered susceptible to nucleophilic attack by the presence of one or more nitrogen atoms in the ring or by the presence of one or more electron withdrawing groups (in other words one or more of Ra, R" Ra, R9, R,o, R", R, 2, R, 3, or R" are halogen, -CF,, vitro, cyano, alkoxycarbonyl, amidocarbonyl, etc.) attached to the ring. Values for A, B, D, E, F, G, I, J, K, and Re, R,, Re, R9, R,o, R", R,z, R", and R" may be selected from those described previously. Solvents suitable for use with the activated aromatic or heterocylic compounds include, for example, dimethylformamide, N-methypyrrolidinone, or methylene chloride and a base (for example triethylamine, 4-dimethylaminopyridine, sodium or potassium carbonate, SUBSTITUTE SHEET (RULE 26) _, 2_ sodium hydride) may be used to facilitate the process if desired. Preferred solvents depend on the solubility of the reagents and the selection thereof would be known to one skilled in the art. These alkylation or acylation reactions are carried out nt temperatures of between about 0°C to about 200°C depending on the nature of the reaction. Preferred temperatures are between about 50°C to about 125°C for these reactions.
The alkylation and acylation procedures described above can also be useful in synthesizing of intermediates of formula V.
Compounds of formula I where Rz is one of the claimed alkyl, alkenyl, or alkynyl moieties can be prepared by reaction of compounds of formula I where Rz is CF,SO, with an appropriate olefin or acetylene compound in the presence of a palladium catalyst. The selection of appropriate olefin or acetylene depends on the alkyl, alkenyi, or alkynyl moiety desired in the end product, as would be appreciated by one skilled in the art. The alkenyl and alkynyl substituted compounds can be produced using the following reaction scheme:
Rlkene, or Rlkyne F'?=~F3S~3_ CatdlySt R1 R~=substituted or '- ~ ~ ~ unsubstituted C
alkenyl or alkynyl as ~ ~ def i ned above SUBSTITUTE SHEET (RULE 26) '~1~845~
,1_ The catalyst may be selected from those typically employed for the so-called Heck reaction (palladium acetate, palladium chloride, bis (acetonitrile) palladium chloride, for example). The reaction is carried out neat or in a reaction inert solvent such as acetonitrile, dimethyfformamide, or N-methylpyrrolidinone. The reaction is conveniently run at 20°C to 160°C, preferably 60°C to 130°C.
The details of reactions of this type have been well described in the literature (Organic Reactions 1982, 27, 345).
The synthesis of compounds having the claimed alkyl moieties require the additional step of reducing the product of the reaction discussed in the previous paragraph. The reduction is performed using standard methods known in the art.
The Heck reaction can also be useful in the synthesis of intermediates of formula V, as is known in the art.
The compounds of formulae I and intermediates of formula V where R~ is CF,SO, can be prepared by reacting the corresponding Rz substituted hydroxy SUBSTITItTE SHEET (RULE 26) t' 1~8 ~3~3 _13-compounds of formulae I or V with an activated form of trifiic acid, for example, triflic anhydride, acid chloride, N-phenyttrifluoromethanesulfonimide, preferably triflic anhydride, typically in the presence of a base, such as, for example, triethylamine or diisopropylethylamine, preferably triethylamine. The reaction may be run in an inert solvent, such as, tetrahydrofuran or methylene chloride, at a temperature of from about -78°C to about 25°C, preferably below about 0°C. This procedure is known in the art, as shown, for example, in J. Amer. Chem. Soc., 1987, 109, 5478.
A method to prepare the compounds of formula I where Rz is R, or R,(CHz)b(C=O)(CHz)~ is accomplished by reacting compounds of formula I where Rs is trimethylstannyl or tributylstannyl with an aryl or vinyl halide, or an aryl or vinyl triflate, or an aryl or alkyl acid chloride or a heteroaryl halide or triflate in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium, and is shown in the following reaction scheme:
Ri Acid Chloride, Aryl Halide or i + Tr i f l ate , He ternary l i Halide or Triflate I
',=~1e3.'-n- ,Bu3Sn-' R =R
w w R4(CH2)b(C=0)(CH2)~_ 'I where c =0 and R4 ~ ' is as defined above The procedures and conditions to carry out this reaction are known to those in the art, for example, in Angew. Chem. Int. Ed. Engl., 1986, 25, 508. . The triflate variant of this reaction is also known in the art, for example, in J. Amer. Chem.
Soc., 1987, 109, 5478. A further variation of this type of process which uses an alkyl or aryl halide in the presence of carbon monoxide gas and a palladium catalyst is also known, for example, in J. Amer. Chem. Soc., 1988, 110, 1557.
SUBSTITUTE SHEET (RULE 26) X158 ~5'~
It will be recognized by one skilled in the art that the coupling reactions described above may also be used to prepare the intermediates of formula V.
The stannane compounds I and V may be prepared from the compound I (Rz being CF,SO,) following known literature procedures (J. Amer. Chem. Soc.,1987, 109, 5478) .
A method to prepare compounds of formula I where R~ is R4 is accomplished by reacting compounds of formula I where R2 is bromo, iodo, or -OSOZCF, with an arylstannane, arylboronic acid, heteroaryl boronic acid, or heteroarylstannane in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium, in an inert solvent, and is shown in the following scheme:
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 ~14-I
R~ , w arylstannane or ~ + heteroarylstannane -or the corresponding Rz - Br , I , or -OS02CF3 boron i c ac i ds I
R2 - Ra The procedures and conditions to cant' out this reaction are known to those skilled in the art, for example, in Angew. Chem. Int. Ed. Engl., 1986, 25, 508. The triflate variant of this reaction is also known in the art, for example, in J. Am. Chem. Soc., 1987, 109, 5478. The required arylstannanes or heteroarylstannanes are available by methods known to one skilled in the art, for example, in J. Am. Chem. Soc, 1987, 109, 5478.
The procedure and conditions for boronic acid couplings are described in J.
Org.
Chem. 1993, 58, 2208.
A method of preparing compounds of formula I and intermediates of formula V where RZ is -O-R, is to react corresponding compounds of formula I or intermediates of formula V where Rz is -OH with alcohols, for example, ethanol or benzyl alcohol, in the presence of triphenylphosphine and diethyl azodicarboxylate in a Mitsunobu reaction. Mitsunobu reactions are known in the art, for example, as disclosed in Synthesis 1981, 1.
Further compounds of formula 1 where RZ is R,-(CH~)e O-(C=O)-(CHz)~ or R4(CHZ)e NH-(C=X)-(CHZ)~ and c is 0 may be prepared by reaction of compounds of the formula I where Rz is OSOzCF, with an alcohol or an amine and carbon monoxide in the presence of a palladium catalyst. Hydrolysis of the resulting esters or amides to SUBSTITUTE SHEET (RULE 26) the corresponding acids and treatment following the general procedures outlined in EP
0 438 230 A2 further allow the preparation of additional compounds of formula I where R~ is -R, and R, is of formula XVI [e.g., a (1,2,4-oxadiazol-5-yl)-naphthalenej.
Compounds of formula I may also be prepared using standard functional group manipulations known in the art and which are disclosed in various standard synthetic chemistry texts. Examples of these are discussed below.
When RZ is R,(CH~)b(C=O)(CHz)~-, it may be reacted with a reducing agent, to yield the corresponding alcohol. Standard methods known in the art can be used.
Useful reducing agents include sodium borohydride, lithium aluminum hydride, or borane (or any of its complexes).
SUBSTITUTE SHEET (RULE 26) Compounds of formula I where the Rz substituent includes a ketone or ester carbonyl moiety may be treated with organometallic agents, such as alkyl- and nryi lithiums, or Grignard reagents using methods known in the art. In this reaction, the resulting compounds will be tertiary alcohols (Rz= -C(OH)R,RS).
When R2 contains an amide group, treatment with a reducing agent, such as, for example, lithium aluminum hydride or borane using known methods, produces the corresponding alkylated (or aralkylated) secondary or tertiary amines.
Another example of the interconversion of compounds of formula I is the reduction of a vitro group of an Rz substituent including a nitrophenyl or nitropyridyl group to the corresponding amine. For example, as shown below, r~0~ ~ R1 NH2 H R1 N w W W N w ' I i i ~ ~Z ~ i where R, and Z are as defined above, the reaction may be carried out using known vitro group reducing agents and methods, for example, hydrogenation over noble metal catalysts (palladium or platinum on a support, such as carbon, 'rf desired) or by dissolving metal reduction.
In a further example of the interconversion of the compounds of formula I, the product of the previous reaction scheme may be cyclized with, for example, dimethylformamide dimethyl acetal or methyl orthoformate to produce fused imidazole compounds of formula I, as shown below, SUBSTITUTE SHEET (RULE 26) X15845?' trialkyl orthoformate w N w w or OMF-acetal I ~Z I ~ i or diethyl ethoxymethylene malonate, or ethoxymethylene-malononitr~le to N=~ Ri N
is ~Z
The reaction may be carried out in an inert solvent, such as, for example, dimethylformamide, ethanol, or dimethyl sulfoxide, preferably dimethylformamide. The 20 reaction is run at a temperature of from about 20 °C to about 125°C. If desired, an acid catalyst, such as, p-toluenesulfonic acid or camphor sulfonic acid, preferably p-toluenesulfonic acid, may also be used to facilitate the reaction. In some cases the SUBSTITUTE SHEET (RULE 26) 5g~5'~
~1 amidine compounds of formula I can be isolated, especially when the acid catalyst is not used.
Another method to carry out the reaction shown in the previous scheme employs diethyl ethoxymethylenemalonate, ethoxymethylenemalononitrile, or related reagents preferably ethoxymethylenemalononitrile, as the cyclization reagent.
This reaction may be run in an inert solvent, such as, acetic acid, ethanol, or isopropanol, preferably isopropanol or acetic acid. The reaction temperature should be from about 25°C to about 150°C. The preferred temperature is the reflux temperature of the solvent for convenience and to decrease the reaction time.
Compounds of formula I where R, is tetrahydropyridine, piperidine, or azacycloalkylmethyl may be prepared from 8-bromo-fi-tetralone, which is known in the art, for example in U.S. Patent No. 4,897,405, as shown in the following reaction scheme:
SUBSTITUTE SHEET (RULE 26) Br ~ \
+ (PhCH~)~NH
Br Br ( PhCHz)z (PhCHz)z / \ / \
/ ~ \ /
X XI
Br BOC
~ Pr~CH2~2N
/ \
\ / /
XI SnMe3 °hC H2 ~,N~ \
\ /
I R1=Formula III
/ \ / \
\ / \ /
I R1=Formula III I R1=Formula III
SUBSTITUTE SHEET (RULE 26) The 8-bromo-fi-tetralone is first reacted with an amine, for example, dibenzylamine to form an enamine X using the same procedure disclosed previously on page 8. The enamine X can be dehydrogenated as described above on page 9, chloranil being the preferred reagent with these particular reactants, to yield 1-bromo-7-amine substituted naphthalenes XI. Selection of an appropriate amine for the enamine-forming step would be apparent to one skilled in the art, for example, diallylamine and dibenzylamines for instance. Compounds XI can be then treated with vinylstannanes, for example, 1-BOC-4-trimethylstannyl-1,2,5,&tetrahydropyridine (BOC=tert-w. X15845?' _17-butyloxycarbonyl), shown in the above scheme, in the presence of a catalyst.
Palladium is the preferred catalyst, for example (Ph,P),Pd or PdZ(dba), and the reaction follows the same procedures as described above on pages 12 to 14, where R, is tetrahydropyridine in a so-called Stille and Heck reactions.
Compounds of formula I where R, is piperidine can be prepared by catalytic hydrogenation of the tetrahydropyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon as the catalyst.
Compounds I where R, is piperidine or tetrahydropyridine can be produced, for example, by removal of the benzyl groups (when R~ is dibenzylamino) by catalytic hydrogenolysis, using a suitable catalyst such as palladium hydroxide, palladium on carbon, or platinum on carbon, preferably palladium hydroxide. The reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a erotic acid, such as acetic acid or HCI. The preferred acid is acetic acid.
In this case, the resulting compounds are of formula I where R~ is amino. The amino group can be derivatized using standard techniques known in the art and as described previously on pages 10 to 16 to afford further compounds of formula I with substituted amines.
Compounds of formula XI from the previous reaction scheme may also be treated with alkyllithium reagents, for example, butyllithium, sec-butyllithium or tert-butyllithium, preferably butyllithium in an inert solvent, as shown below, SUBSTITUTE SHEET (RULE 26) Br (PhCH2)2N /
+ Butyllithium ~ /
XI
Li (PhCH2>2N / \
\ /
XII
Fhi_H2)2N , \
\ /
~ P1=Formul a I I I OR IV
Suitable solvents include, for example, ether or tetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures range from about -110°C to about 0°C. The intermediate lithium anions of formula XII thus formed may then be further reacted with a suitable electrophile, selection of which depends on the desired substituent at the R, SUBSTITUTE SHEET (RULE 26) -1 &
position. Suitable electrophiles to prepare compounds I where R, is formula III or IV
include, for example, carbonyl derivatives or alkylating agents (e.g., 1-BOC~-piperidone, 1-BOC-prolinal or 1-FMOC-2-chloromethylpyrrolidine (FMOC=fluorenylmethoxycarbonyl)).
In the case where an aldehyde or ketone is used as the electrophile, the intermediates XIII, XIV, or XX which are formed require that the hydroxy group be removed so as to result in compounds of formula I as shown below, BOC
~ N
HO r, (PhCH2)2N , ~ (PhCH2)2 I i ~ I i XIII I R1=Formula IV
BOC
N, <>
a Pr.[H i N I
z 2 / HO \ (PhCH2)zN
I
w i w i XIV I R1=Formula III
BOC
'N
HO Ri Pr~i'H, ~,N \ CPhCH2)2N
' i w I
XX I R1=Formula V
SUBSTITUTE SHEET (RULE 26) WO 94/21619 PCT/US94/01206 -_..
2 ~. 5 8.~ 5'~ -, 8n -This step may be accomplished by one of several standard methods known in the art. For example, a thiocarbonyl derivative (for example a xanthate) may be prepared and removed by a free radical process, both of which are known to those skilled in the art. Alternatively, the hydroxyl group may be removed by reduction with SUBSTITUTE SHEET (RULE 26) -1 s.
a hydride source such as triethyisilane under acidic conditions, using such as, for example, trifluoroacotic acid or boron trifluoride. The reduction reaction can be performed neat or in a solvent, such as methylene chloride. A further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using standard methods. The leaving group is then removed with a nucleophilic hydride, such as, for example, lithium aluminum hydride. This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.
Also, a reducing agent may be used to reductively remove of the benzylic substituent.
Suitable reducing agents include, for example, Raney nickel in ethanol, or sodium or lithium in liquid ammonia. Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol XlII, XIV, or XX to an olefin with a reagent such as Burgess salt tJ. Or4. Chem., 1973, 38, 26) followed by catalytic hydrogenation of the double bond under standard conditions with a catalyst such as palladium on carbon. The alcohol may also be dehydrated to the olefin by treatment with acid such as p-toluenesutfonic acid. For Xlll the free radical procedure is preferred because it preserves the stereochemical integrity of the chiral center. For XIV or XX the Burgess salt or acid dehydration procedures are preferred.
In the case where R= is, for example, dibenzylamino, additional compounds of formula 1 may be prepared by hydrogenolysis and derivatization as described above on pages 10 to 16.
8-bromo-(3-tetralone, discussed earlier, may also be utilized to form other compounds of formula I, as shown below, * Trade-mark a 215 __ Br Br / w Br F 0..
P=H or Protecting Group w /
,5 Ri P 0-, i R1 - Formula or IV
R1 Ri Fn Rz ~w ~ / w / ~ I /
1 - Formula I R1 - Formula III or IV
I I I or I V
Rz - R40,R4, alkenyl alkynyl (substituted and unsubstituted SUBSTITUTE SHEET (RULE 26) WO 94/21619 215 8 ~ 5 7 PCT/US94/01206 8-bromo-f3-tetralone is first dehydrogenated to form 1-bromo-7-hydroxynaphthalene using an oxidizing reagent, such as, for example, elemental sulfur as described above on page 8 or N-bromosuccinimide. An appropriate protecting group is then used to protect the hydroxyl group if desired, formation and selection being w'tthin the knowledge of one skilled in the art (e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 ). This is followed by subsequent replacement of the bromo substituent using methods described previously on pages 16 to 18. After replacement of the bromo substituent, the hydroxyl protecting group may be removed using standard chemistry, and the free hydroxyl group may be derivatized as described above on pages 10 to 14 to afford compounds of formula I
wherein RZ is attached to the naphthalene ring via a carbon or oxygen atom. In some cases the protecting group may also serve as an activating group for further transformations, CF,SO, for example, as described earlier on pages 12 to 14 or may simply be the final Rz moiety.
Unless indicated othervvise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or SUBSTITUTE SHEET (RULE 26) ~15845~ -2,-acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the fomnula I which are also acidic in nature, e.g., where R~ contains a carboxylate, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particular, the sodium and potassium salts.
These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction of maximum product of yields of the desired final product.
The compounds of the formula I and the pharmaceutically acceptable salts thereof (hereinaffer, also referred to as the active compounds of the invention) are useful psychotherapeutics and are potent serotonin (5-HT, ) agonists and antagonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, chronic paroxysmal hemicrania and headache associated with vascular disorders, pain, and other disorders arising from deficient serotonergic neurotransmission such as Alzheimer's disease. The compounds can also be used as centrally acting antihypertensives and vasodilators.
The affinities of the compounds of this invention for the various serotonin 1 receptors are evaluated using standard radioligand binding assays as described in the literature. The 5-HT,A affinity is measured using the procedure of Hoyer et al. (Brain Res., 1986, 376, 85). The 5-HT,~ affinity is measured using the procedure of Pazos et SUBSTITUTE SHEET (RULE 26) 2158 ~5~' al. (Eur. J. Pharmacol., 1985, 106, 539). The 5-HT,o affinity is measured using the procedure of Heuring and Peroutka (J. Neurosci., 1987, 7, 894).
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pham~aceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.
almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbid acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
SUBSTITUTE SHEET (RULE 26~
'~1~8 ~~~ -23-The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., migraine) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or ~puff" of aerosol contains 20Ng to 1000Ng of the compound of the invention.
The overall daily dose with an aerosol will be within the range 100Ng to 10 mg.
Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million (a) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF
refers to dimethylformamide. Chromatography refers to column chromatography performed using 32-63 Nm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25°C. All non-aqueous SUBSTITUTE SHEET (RULE 26) reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure implies the use of a rotary evaporator.
The terms 1-piperazinyl and piperazin-1-yl, t-piperidinyl and piperidin-1-yl, and 3-pyrrolidinyl and pyrrolidin-3-yl are used interchangeably throughout this document.
Triflate refers to -OSOzCF3 or CF,SO~.
SUBS?ITUTE SHEET (RULE 26) Example 1 7-Benzamido-1-14-methyl-1-piperazinyl)-naphthalene 7-Amino-a-tetralone (42.15 g, 0.262 mol) was dissolved in dry THF (1000 mL) and triethylamine (38.3 mL, 0.288 mol) was added. The mixture was chilled to 0°C and benzoyl chloride (33.4 mL, 0.288 mol) was added dropwise with a THF (10 mL) rinse.
The mixture was mechanically stirred overnight, then the solvent was removed with a nitrogen stream. The residues were taken up in methylene chloride and extracted with 1 N HCI, water, saturated sodium bicarbonate, and brine. The organic phase was further dried over calcium sulfate and concentrated to a solid mass.
Recrystallization from ethanol (650 mL) yielded 52 g of 7-benzamido-a-tetralone. Concentration of the mother liquors yielded another 6 g for a total yield of 58.9 g (8596): mp 153-156°C.
Analysis calculated for C"H"NOz: C, 77.25; H, 5.34; N, 5.30. Found: C, 77.05;
H, 5.57; N, 5.30.
7-Benzamido-a-tetralone (5.0 g, 18.95 mmol) was dissolved in dry THF (107 mL) and N-methyl-piperazine (6.3 mL, 56.8 mmol) was added. The solution was cooled to -78°C and titanium tetrachloride (2.5 mL, 22.75 mmol) in methylene chloride (30 mL) was added dropwise. The mixture was stirred overnight and during this time a fine green precipitate formed. The solvent was removed under a stream of nitrogen and the residue was stirred vigorously in a mixture of ethyl acetate and 5N ammonium hydroxide for 2 hours. The solid which formed was collected, washed with ethyl acetate and then ether, and dried in vacuo. The filtrate was discarded. The solid was vigorously stirred with 1 N sodium hydroxide (100 mL) and methylene chloride (100 mL) for 2 hours. The solid which did not dissolve was removed by filtration. The phases were separated from the filtrate and the organic layer was washed with brine, dried over calcium sulfate and concentrated to give 1.01 g of product. The solid was now stirred with dimethyl sulfoxide (DMSO, 150 mL) for 2 hours and filtered again. The undissolved material was discarded. The DMSO was removed at reduced pressure and the residue was taken up in methylene chloride. This organic solution was treated with brine which removed the last traces of DMSO from the organic phase and caused immediate precipitation of 2.29 g more product which was collected and dried. The phases were separated from the filtrate. The organic layer was dried over sodium sulfate and concentrated to leave 2.13 g of light tan solid product. In this fashion 5.43 g, 83°~6 of 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalenewas obtained; 'H
NMR
SUBSTITUTE SHEET (RULE 26) 15~~57 (CDC1~) d 7.88 (dd, J = 1.5, 8 Hz, 2H), 7.77 (br s, 1 f-(), 7.59 (d, J = 2 Hz, 1 H), 7.56-7.46 (m, 4H), 7.16 (d, J = 8 Hz, 1 H), 5.32 (t, J = 4.5 Hz, 1 H), 2.88 (br s, 4H), 2.69-2.55 (m, 6H), 2.36 (s, 3H), 2.27-2.17 (m, 2H).
A mixture of xylene (500 mL) and 10 96 Palladium on carbon (2.0 g) was refluxed overnight with azeotropic removal of water by means of a Dean-Stark trap containing 4 ~ molecular sieves. The mixture was cooled to room temperature and 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene (5.44 g, 15.67 mmol) was added. The mixture was heated at reflux for 2 hours, cooled, and filtered through a Celite pad. The filtrate was concentrated in vacuo and purified by silica gel flash chromatography (1.5 1 O x 4 inches). Elution with 50 to 8596 ethyl acetate/hexane gave 7-benzamido-a-tetralone (0.636 g). Continued elution with 9596 ethyl acetate / hexane and pure ethyl acetate gave 1.37 g of title product followed by 1.95 g of a 2:1 mixture of title product and 7-benzamido-1-(4-methylpiperazinyl)-1,2,3,4-tetrahydronaphthalene. The 1.95 g mixture was rechromatographed as above to yield 1.0 g more pure title product. In this manner 2.37 g, 4396 was obtained: mp 173-175°C. Analysis calculated for C~~H1~N,0: C, 76.49; H, 6.71; N, 12.16. Found: C, 75.94; H, 6.39; N, 11.95.
Exnmole 2 7-Amino-1-(4-methyl-1-piperazinyll-naphthalene 7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene (the product from example 1, 3.75 g, 10.87 mmol) was slurried in 6N HC) (a mixture of concentrated HCI
(25 mL) and ethanol (25 mL)) (50 mL) and refluxed for 3.5 hours. The mixture was cooled and brought to pH 10 with 1 N sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over calcium sulfate and concentrated to afford 2.44 g (92 96) of the title product which was suitable for use in further reactions without purification. A sample was recrystallized from isopropyl alcohol for analysis: mp 157-159°C; 'H NMR a 7.G5 (d, J = 8.5 Hz, 11i), 7.44 (d, J = 8 Hz, 1 ti), 7.35 (d, J = 2 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 I-i), 7.04 (d with long range coupling, J = 7 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 )i), 3.88 (br s, 3H), 3.12 (br s, 4H), 2.42 (s, 3H). Analysis calculated for C,SH,9N,: C, 74.65; H, 7.94; N, 17.41.
Found: C, 74.79; H, 8.14; N, 17.41.
*Trade-mark ,._ Example 3 7-(2-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene A solution of 7-amino-t-(4-methyl-1-piperazinyt)-naphthalene (0.197 g, 0.817 mmol) and triethylamine (0.217 mL, 1.63 mmol) in acetonitrile (10 mL) was chilled to 0°C and 2-naphthoyl chloride (0.311 g, 1.63 mmol) was added. The solution was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The mixture was stirred vigorously with saturated sodium bicarbonate for 2 hours and the phases were separated. The organic Isyer was dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1 x 3 inches). Ethyl acetate/hexane gradient elution of from 25:75 to 75:25 followed by ethyl acetate and finally 596 ethanol/ethyl acetate gave 0.31 g of light yellow foam. Trituration with hexane yielded 0.235 g (7296) of the title product as an amorphous solid: mp 95-130°C. High resolution mass Spectrum (HRMS) m/e calculated for CzaHz5N30: 395.1994. Observed m/e: 395.1981.
Example 4 7-(3-Nitrobenzamido)-1-(4-methyl-1-piaerazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3-nitrobenzoyl chloride (0.127 mL, 0.684 mmot) in acetonitrile (10 mL) with an overnight reflux. The product was purified by silica gel flash chromatography followed by recrystallization from ethyl acetate to yield 0.116 g (4796) of the title product: mp 182-184°C. Analysis calculated for CZ~H~~N,O,:
C, 67.68; H, 5.68; N, 14.35. Found: C, 67.47; H, 5.64; N, 14.08.
Example 5 7-~1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.227 g, 0.94 mmol) and triethylamine (0.133 mL, 0.1.32 mmol) and 1-naphthalenecarboxylic acid chloride (0.25 g, 1.32 mmol) in acetonitrile (10 mL) with stirring overnight at room temperature. The product was purified and after chromatography and recrystallization from ethyl acetate yielded 0.213 g (5796) of the title compound and had; mp 217-218°C. Analysis calculated for C~aH~5N,0: C, 78.96, H, 6.37; N, 10.62. Found: C, 78.66; H, 6.33; N, 10.48.
SUBSTITUTE SHEET (RULE 26) Example 6 7-(3-Chlorobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.0768 (2096) of the title compound: mp 147-148°C. HRMS m/e calculated for CZZH=zCIN~O: 379.1448. Observed m/e:
379.14473. Analysis calculated for Cz~Hz~CIN,O: C, 69.56; H, 5.84; N, 11.06.
Found:
C, 68.95; H, 5.81; N, 10.96.
Example 7 7-(3 5-Dinitrobenzamidol-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 3 from 7 amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from acetonitrile to yield 0.17 g (6396) of the title compound: mp 254-256°C. Analysis calculated for C~~Hz,Ns05: C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Example 8 7-(4-Chlorobenzamidol-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride (0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from ethyl acetate to yield 0.17 g (4396) of the title compound as a white solid mp 174-175°C. HRMS m/e calculated for CzzHZ2CIN30:
379.1448. Observed m/e: 379.1465. Analysis calculated for CzzHzzCIN30: C, 69.56;
H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
SUBSTITUTE SHEET (RULE 26) s ~,1 Example 9 7-(3-Cyanobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.213 g, 0.883 mmol) and triethylamine (0.258 mL, 1.94 mmol) and 3-cyanobenzoyl chloride (0.322 g, 1.94 mmol) in acetonitrile (10 mL) with stirring at reflux for 2 hours and then at room temperature overnight. The mixture was concentrated and the residue was taken up in methylene chloride.
This organic solution was washed with 0.5 N sodium hydroxide, dried over calcium sulfate and concentrated. The product was isolated by silica gel flash chromatography and recrystallization from isopropyl alcohol to yield 0.184 g of (6096) of the title compound:
mp 220-222°C. Analysis calculated for CZ,HZZN,O: C, 74.57; H, 5.99; N, 15.12.
Found: C, 74.42; H, 5.78; N, 14.96.
Example 10 7-(4-Hydroxvbenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.118 g, 0.489 mmol) and triethylamine (0.13 mL, 0.98 mmol) in acetonitrile (10 mL) was chilled to 0°C
and 4-triisopropylsilyloxybenzoyl chloride (0.16 g, 0.51 mmol) dissolved in methylene chloride was added all at once. The mixture was gently refluxed overnight;
then 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.038 g, 0.16 mmol), 4-triisopropylsilyloxybenzoyl chloride (0.5 g, 1.6 mmol), and triethylamine (0.13 mL, 0.93 mmol) were added. The reaction was refluxed for an additional 24 hours, cooled and the solvent was removed at reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and stirred vigorously for 5 hours. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1 x 3.5 inches). Elution with 2596 ethyl acetate/hexane removed unweighed recovered acid chloride. Continued elution with an ethyl acetate/hexane gradient of from 1:3 to 3:1 followed by 10096 ethyl acetate gave 0.238 g of 7-(4-triisopropylsilyloxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene as a viscous tan oil.
The product of the above reaction was dissolved in dry THF (10 mL) and tetrabutylammonium fluoride (0.47 mL, 0.47 mmol, 1 M in THF solution) was added dropwise. The solution darkened and was stirred 2 hours followed by addition of 0.2 SUBSTITUTE SHEET (RULE 26) mL more tetrabutylammonium fluoride. After stirring an additional 3 hours, the solvent was removed and the residue was taken up in ethyl acetate. This organic phase was washed with water and brine, dried over calcium sulfate and concentrated to a white foam. This foam was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with ethyl acetate/hexane of from 1:3 to 3:1 gave nil. Continued elution with 5%
ethanol/ethyl acetate gave first the title product (0.04 g) which was about 80 % pure followed by an additional 0.02 g of pure product. The 0.02 g sample was triturated with ether / hexane and yielded 0.006 g (1.9%) of title product as a tan solid: mp 160°C. HRMS m/e calculated for CzzHz3N~0~: 361.1789. Observed m/e:
361.1787.
1 p Example 11 7-Benzamido-1-( 1-aiperazinyll-naphthalene The title product from Example 1 (0.50 g, 1.45 mmol) was dissolved in methylene chloride (10 mL) and chilled to 0°C. 1-chloroethyl chloroformate (0.156 mL, 1.45 mmol) was added via syringe. The mixture was allowed to come to room temperature and then refluxed 3 hours. Additional 1-chloroethyl chloroformate (0.1 mL, 0.93 mmol) was added and the mixture was further refluxed overnight. Methanol (tOmL) was added and the reaction was refluxed for 2 hours. The mixture was concentrated and the residue was taken up in methylene chloride and extracted with 1 N NaOH and brine. The organic phase was dried, concentrated onto silica gel, and flash chromatographed (1 x 4 inches silica gel). Gradient elution with ethyl acetate /
hexane of from 1:1 to 10096 ethyl acetate followed by elution with 2 to 10 96 ethanol/0.1 ammonium hydroxide/ethyl acetate gave recovered unweighed starting material.
Continued elution with 15% methanol / 0.1 % ammonium hydroxide/ethyl acetate gave 0.32 g of the title product as a clear colorless oil which partially crystallized on standing.
Trituration with ether gave 0.13 g (2796) of the title compound as white crystals: mp 141.5-144°C; 'H NMR a 8.58 (br s, 1H), 8.04 (br s, 1H), 7.95 (dd, J =
8, 1.5 Hz, 2H), 7.84 (d, -J = 9 Hz, 1 H), 7.68 (dd, J = 2, 9 Hz, 1 H), 7.62-7.49 (m, 4H), 7.37 (t, J = 8 Hz, 1 H), 7.12 (d, J = 7 Hz, 1 H), 3.32-3.22 (m, 5H), 3.16 (br s, 3H), 2.40 (br s, 1 H, exchanges with DSO). HRMS m/e calculated for C~,Hz,N30: 331.1680. Observed m/e:
331.1682.
SUBSTITUTE SHEET (RULE 26) Example 12 7-(4-Chlorobenzamido-1-(1-piperaziny~-naphthalene The title product of example 8 (1.69 g, 4.62 mmol) and 1,8-bis (dimethylamino)naphthalene (3.47 g, 16.2 mmol) were dissolved in dichloroethane (160 mL) and chilled to 0°C. 1-Chloroethyl chloroformate (0.8 mL, 7.4 mmol) was added and the solution was refluxed overnight. The mixture was concentrated and flash chromatographed on silica get (2 x 3 inches). Elution with 10 to 2596 ethyl acetate /
hexane gave first an unweighed impurities and then 1.56 g of a mixture of 1,8-bis (dimethylamino)naphthalene and the urethane intermediate (1:1.2 ratio). The mixture was dissolved in methylene chloride and extracted repeatedly with pH 5.8 buffer. The organic layer was dried over calcium sulfate and concentrated to give 0.98g of base free intermediate urethane suitable for subsequent reaction.
The intermediate was dissolved in methanol (40 mL) and refluxed 5 hours. The mixture was concentrated and the residues were taken up in methylene chloride.
The organic phase was washed with 0.5 N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1 x 2 inches).
Elution with 5 to 1596 methanol/0.19o ammonium hydroxide/ethyl acetate gave 0.667 g of oily solid. This semi-solid recrystallized from methanol to give 0.54 g (3296) of the title compound as tan crystals in hero crops: mp 210-211 °C. HRMS m/e calculated for Cz, H~°CIN~O: 365.1290. Observed m/e: 365.1294.
Example 13 7-(1-Naphthylmethylamino)-1-(4-methyl-1-piperazinyl)-naphthalene To a cold (-78°C) mixture of lithium aluminum hydride (0.012 g, 0.316 mmol) in THF (5 mL) was added the product of example 5 (0.10 g, 0.256 mmol) all at once. The mixture was allowed to warm to ambient temperature and stir 5 hours. The mixture was refluxed overnight. The mixture was cooled to 0°C and additional lithium aluminum hydride (0.014 g, 0.368 mmol) was added and the mixture was refluxed 5 hours more.
The mixture was again cooled to 0°C and carefully quenched with water and the solvent was removed. The residue was taken up in ethyl acetate, dried over sodium sulfate, concentrated, and flash chromatographed on silica gel (1 x 2.5 inches).
Elution with a gradient of 50 to 85% ethyl acetate/hexane gave 0.05 g of title product.
Recrystallization from ether gave 0.018 g (18.596) of title product as a white solid: mp 140-141 °C. HRMS m/e calculated for CzeH~,N3: 381.2199. Observed m/e:
381.2217.
SUBSTITUTE SHEET (RULE 26) ~2- 215857 Example 14 7-(Benzylamino)-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 1 (0.12 g, 0.348 mmol) was dissolved in toluene (4 mL) and borane-dimethyl sulfide (0.3 mL, 3 mmol) was added. The mixture was refluxed 3 hours and cooled. 6 N HCI and ethyl acetate were added and the mixture was refluxed until all the solids had dissolved. The organic phase was separated and discarded. The aqueous phase was made basic with 4 N NaOH and extracted with methylene chloride. This organic phase was washed with brine, dried over calcium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (0.5 x 4 inches). Elution with 5096 and then 7596 ethyl acetate/hexane gave 0.053 g of product. This material was further purified by trituration with hexane to provide 0.03 g, (26 96) of the title product as a tan powder: mp 115-117°C; 'H NMR
a 7.64 (d, J = 8.5 Hz, 1 H), 7.46-7.24 (m, 6H), 7.14 (t, J = 7.5 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 7.00 (ss, J = 1, 7.5 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 H), 4.50 (br s, 2H), 4.34 (br m, 1 H), 3.01 (br s, 4H), 2.53 (br s, 4H), 2.38 (s, 3H). Analysis calculated for C~~Hz5N3~0.5 HzO: C, 77.61; H, 7.70; N, 12.34. Found: C, 77.78; H, 7.48; N, 12.07.
Example 15 7-Trifluoroacetamido-1-(4-methyl-1-piaerazinyl)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g,1.04 mmol) and triethylamine (0.15 mL, 1.14 mmol) in dry THF was chilled to 0°C
and treated with trifluoroacetic anhydride (0.16 mL, 1.14 mmol). The mixture was allowed to warm to ambient temperature and stir overnight. Triethylamine (0.25 mL, 1.88 mmol) and trifluoroacetic anhydride (0.16 mL, 1.14 mmol) were added and the solution was stirred another 24 hours. Triethylamine (0.15 mL, 1.14 mmol) was added and the solution was stirred 2 hours more. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was washed with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated.
The product was purified by silica gel flash chromatography (1 x 2 inches).
Ethyl acetate/hexane gradient elution of from 1:1 to 3:1 gave 0.15 g of oily product.
Trituration with hexane gave 0.11 g (3196) of the title product. A sample recrystallized from methyl cyclohexane was submitted for analysis: mp 159-160°C. HRMS
m/e calculated for C"H,eF3N30: 337.1400. Observed m/e: 337.13867. Analysis calculated for C"H,BF,N,O: C, 60.53; H, 5.38; N, 12.46. Found: C, 60.04; H, 5.27; N, 12.05.
SUBSTITUTE SHEET (RULE 26) Example 16 7-Acetamido-1-(4-methyl-1-piperazinyi)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.238 g, 0.986 mmol) and triethylamine (0.144 mL, 1.08 mmol) in acetonitrile (12 mL) was chilled to 0°C and acetyl chloride (0.077 mL, 1.08 mmol) was added all at once.
The mixture was heated to reflux for 7 hours and cooled to room temperature. (TLC with methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated to a light tan solid (0.115 g).
Trituration with hexane gave 0.09 g (3396) of the title product as a tan solid: mp 173-177°C. A
sample recrystallized from ethyl acetate was submitted for analysis: mp 177-180°C.
HRMS m/e calculated for C"H~,N30: 283.1682. Observed m/e: 283.1678.
Example 17 7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 16 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.182 g, 0.755 mmol) and triethylamine (0.201 mL, 1.51 mmol) and hexanoyl chloride (0.211 mL, 1.51 mmol) in acetonitrile (10 mL) with an overnight reflux. The product was purified by recrystallization from ethyl acetate/hexane to yield 0.0978 (3796) of the title compound: mp 144-146°C. Analysis calculated for Cz, H~9N,0: C, 74.30; H, 8.61; N, 12.38. Found: C, 73.91; H, 8.52; N, 12.22.
Example 18 7- (p-Toluenesulfonamido)-1-(4- methyl-1-piperazinyl)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.205 g, 0.85 mmol) and triethylamine (0.124 mL, 0.935 mmol) in dry THF (3 mL) was chilled to 0°C
and para toluenesulfonyl chloride (0.178 g, 0.935 mmol) was added all at once.
The mixture was allowed to warm to room temperature and stirred overnight (TLC
with 40%
methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated. Flash chromatography on silica gel (1 x 3 inches) with ethyl acetate/hexane gradient elution of from 5096 to 10096 gave 0.21 g SUBSTITUTE SHEET (RULE 26) 2I584~?
of a light tan solid. The solid was further purified by two recrystallizations from ethyl acetate to yield 0.07 g (2096) of the title product: mp 180-181.5°C.
Analysis calculated for C~~HzSN,OzS: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.55; H, 6.31; N, 10.20.
Example 19 7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.216 g, 0.896 mmol) and phenyl isocyanate (0.222 g, 1.86 mmol) were combined in acetonitrile (14 mL) and refluxed overnight. Phenyl isocyanate (0.106 g, 0.896 mmol) was added and the reaction was refluxed 2 hours more. Upon cooling a tan solid precipitated which was collected and recrystallized ftom methanol/ethyl acetate to give 0.202 g (62%) of the title product; mp 213-214°C. Analysis calculated for Cz~Hz,N,O: C, 73.31; H, 6.71; N, 15.54. Found: C, 73.03; H, 6.55; N, 15.22.
Example 20 7-(Benzvloxycarbonvlamino)-1-~4-methyl-1-piperazinyl)-nachthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate (0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol) was added and the reaction was stirred 5 hours more. The reaction was diluted with methylene chloride and the phases were separated.
The organic layer was washed with brine, dried over calcium sulfate and concentrated to a brown oil which was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with ethyl acetate/hexane of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 596 to 1096 gave 0.29 g of a brown foam.
This residue was recrystallized from ethyl acetate to give 0.095 g (2796) of the title product in two crops; mp 143-144°C. Analysis calculated for Cz,H15N302: C, 73.58; H, 6.71;
N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Example 21 7-((2-Benzyloxycarbonylamino)-acetamidol-1-(4-methyl-1-piperazinyl)-naphthalene N-benzyloxycarbonylglycine (0.69 g, 3.32 mmol) was dissolved in methylene chloride (10 mL) and carbonyl diimidazole (0.54 g, 3.32 mmol) was added. The solution was stirred for 2 hours; then 7-amino-1-(4-methyl-1-piperizinyl)-naphthalene (0.2 SUBSTITUTE SHEET (RULE 26) WO 94!21619 PCT/US94I01206 :-35-g, 0.83 mmol) was added. The solution was stirred overnight. The reaction was extracted with saturated aqueous potassium carbonate and brine, dried over calcium sulfate and concentrated to give white crystals. Recrystallization from ethyl acetate gave 0.187 g (52 96) of the title product as white crystals: mp 187-188°C. Analysis calculated for C~5Hz8N,0,: C, 69.42; H, 6.52; N, 12.95. Found: C, 69.21; H, 6.50; N, 12.79.
Example 22 7-(Benzoylaminothiocarbonylamino?-1-(4-methyl-1-aiperazinyl)-naphthalene To a mixture of ammonium thiocyanate (0.376 g, 4.94 mmol) in acetone (5 mL) was added benzoyl chloride (0.57 mL, 4.94 mmol) dropwise. The mixture (white precipitate) was refluxed 45 minutes which resulted in a yellow heterogeneous solution.
A solution of 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (1.0 g, 4.14 mmol) in acetone (25 mL) was added dropwise (10 mL acetone rinse also added). The mixture was refluxed 4 hours and allowed to stir overnight at ambient temperature. The mixture was concentrated onto silica gel and flash chromatographed (2 x 3.5 inches).
Gradient elution with ethyl acetate/hexane of from 5096 to 10096 gave an unweighed forerun.
Continued gradient elution with 10 to 4096 ethanol/ethyl acetate gave 1.3 g (7796) of title product as a yellow foam which was suitable for use without further purification. The compound was found to slowly decompose at room temperature. A sample recrystallized from ethyl acetate/methylene chloride for analysis: mp 160-250°C. 'H
NMR (DMSOde, D20) a 8.74 (s, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.91 (d, J = 9 Hz, 1 H), 7.70-7.51 (m, 5H), 7.42 (t, J = 8 Hz, 1 H), 7.12 (d, J = 7 Hz, 1 H), 3.11 (m, 4H), 2.79 (br s, 4H), 2.39 (s, 3H). HRMS m/e calculated for Cz,H~,N,OS: 404.1661. Observed m/e:
404.1633.
Example 23 7-(Aminothiocarbonylamino]-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 22 (1.09 g, 2.7 mmol) was slurried in ethanol (10 mL) and a solution of 1.4 g NaOH in water (14 mL) was added. The mixture was refluxed 3 hours; then the ethanol was removed with a stream of nitrogen. The aqueous residue was extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, and concentrated to leave 0.39 g (4896) of the title product. A sample was recrystallized from acetonitrile for analysis: mp 194-SUBSTITUTE SHEET (RULE 26) 195°C. Analysis calculated for C,eHz°N,S~CH,CN~0.5 HzO: C, 62.96; H, 6.67; N, 19.32. Found: C, 62.86; H, 6.71; N, 19.69.
Exempla 24 4-Benzyl-2-(-1-(4-methyl-1-piperazinyl)-7-naphthylaminol-thiazole A mixture of the title product of example 23 (0.225 g, 0.75 mmol) and 1-chloro-phenylacetone (0.188 g, 1.12 mmol) in isopropanol (6 mL) was refluxed 3 hours.
The solvent was removed and the residue was taken up in methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over calcium sulfate, and concentrated onto silica gel for flash chromatography (1 x 3 inches). Gradient elution with 5096 to 10096 ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.283 g of a yellow foam.
Trituration with ethyl acetate gave 0.137 g (4496) of the title product as yellow crystals: mp 157-160°C. Analysis calculated for CzSH~eN,S: C, 72.43; H, 6.32; N, 13.51.
Found: C, 72.55; H, 6.51; N, 13.72.
Example 25 7-(3-Nitro-2-pvridinvlaminol-1-(4-methyl-1-p~erazinyl)-naphthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.2478,1.02 mmol), 2-chloro-3-nitropyridine (0.325 g, 2.05 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were combined in dry DMF (0.15 mL). The solution was refluxed 4 hours then 0.5 mL
more DMF was added and the mixture was allowed to stir at ambient temperature overnight. 2-Chloro-3-nitropyridine (0.105 g, 0.69 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were added and the mixture was refluxed 2 hours more. The solvent was removed in vacuo and the residue was taken up in methylene chloride.
This organic phase was washed with 0.5 N sodium hydroxide and brine; then it was dried over calcium sulfate and concentrated to a red oil which was flash chromatographed on silica gel (1 x 4 inches). Gradient elution with 5096 to 759'o ethyl acetate/hexane followed by elution with 10096 ethyl acetate gave a dark colored oil which crystallized upon addition of ether (2 mL) to yield 0.19 g (5196) as a dark red solid: mp 127.5-129°C. Analysis calculated for C~°Hz,N50Z: C, 66.10; H, 5.82; N, 19.27.
Found: C, 66.04; H, 5.81; N, 19.02.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 ~7-Example 26 7~2.4-Din'ttrophenylamino~-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.05 g, 0.207 mmol) and 2,4-dinitrochlorobenzene (0.75 g, 0.373 mmol) in dry DMF (2 mL) was refluxed 2 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to give 0.0458 (5496) of the title compound: mp 153-154°C. Analysis calculated for Cz, HZ, N50,: C, 61.91; H, 5.20; N, 17.19. Found: C, 61.42; H, 5.10; N, 16.79.
Example 27 7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.212 g, 0.88 mmol), 5-vitro-2-chloropyridine (0.314 g, 1.98 mmol), and 4-dimethylaminopyridine (0.085 g, 0.7 mmol) in dry DMF (2 mL) was refluxed 8 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated 0.5 N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with from 5096 to 9096 ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.136 g of orange oil.
Recrystallization from isopropanol followed by recrystallization from nitromethane gave 0.005 g (1.496) of the title product as orange crystals: mp 121-125°C.
Analysis calculated for Cz°HZ,NSOz~HzO: C, 62.98; H, 6.08; N, 18.36. Found: C, 62.86; H, 5.84;
N, 18.13.
Example 28 7-(2-Nitrophenylaminol-1-(4-methyl-1-piperazinyl)-naphthalene The title product was obtained following the procedure of example 27 by reacting 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.93 mmol), fluoronitrobenzene (0.255 g, 1.8 mmol), and 4-dimethylaminopyridine (0.167 g, 1.37 mmol) in dry DMF (5 mL) with an overnight reflux. The product was isolated by silica gel flash chromatography and recrystallization from ethyl acetate/ether to yield 0.0248 (796) of the title compound as orange crystals: mp 87-94°C; 'H NMR a 9.70 (br s, 1 H), 8.26 (dd, J = 1.5, 8.5 Hz, 1 H), 8.07 (d, J = 2 Hz, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 7.57 (s, J = 8 Hz, 1 H), 7.44-7.32 9m, 4H), 7.16 (dd, J = 1, 7.5 Hz, 1 H), 6.82 (dd, J = 2, 6.5, SUBSTITUTE SHEET (RULE 26) 21.58~r57 8.5 Hz, 1 H), 3.15 (br s, 4H), 2.T0 (br s, 4H), 2.41 (s, 3H). HRMS m/e calculated for C~,H,~N,O=: 362.1738. Observed m/e: 362.1736.
example 29 7-(3-Amino-2-pyridylamino~-1-(4-methyl-1-piperazinylL-naphthalene To a slurry of 1096 palladium on carbon (0.56 g) in ethanol (30 ml-a was added the title product from example 25 (3.38 g, 9.3 mmol) was dissolved in a mixture of ethanol (20 mL), methanol (50 mL), and ethyl acetate (100 mL). The mixture was hydrogenated a1 50 psi for 3 hours. A total of 36 psl of Hi was taken up (35 psi is theory). The mixture was filtered through C elite and the titter pad was rinsed well with ethyl acetate. The filtrate was concentrated to give 3.4 g (10096) of brown crystals which was an ethanolate of the title product which was suitable for further reaction without purification. A sample recrystallized from ethanol for analysis: mp 198-200°C.
Analysis calculated for Cz°H~~NS: C, 72.04; H, 6.95; N, 21.00. Found:
C, 71.72; H, 6.87; N, 20.84.
Exnmple 30 7-f 3-Benzamido-2-pvridvtamino)-1-(4-methY(-1-piperazinyt)-naphthalene The title product from example 29 (0.2 g, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) were dissolved in THF (8 mL) and the solution was chilled to 0°C. Benzoyl chloride (0.09 mL, 0.78 mmol) was added and the mixture was stirred 24 hours at room temperature. The solvent was removed and the residue was taken up in methylene chloride. The organic phase was washed with 1 N NaOH and brine; then it was dried through phase separating paper and concentrated onto silica gel for flash chromatography (1 x 3.5 inches). Elution wish methyfene chloride then 396 methanol/methylene chloride was not productive. Continued elution with 696 methanol/methylene chloride gave first 0.108 g of an impurity and second 0.128 g of product as a tan foam. The foam was further purified by recrystallization from ethyl acetate to yield 0.078 g (3096) of the title product as tan crystals: mp 205-207 ° C.
6W alysis calculated for C?,Hz,N50: C; 74.12; H, 6.22; N, 16.01. Found: C, 73.59; Fi, 5.93; N, 15.54.
Example 31 7-(3-Acetamido-2-pyridylaminol-1-(4-methyl-1-piperazinyl)-naphthalene The title compound was prepared following the procedure of example 30 from ttie product o1 example 29 (0.25 g, 0.75 mmol), acetyl chloride (0.045 mL, 0.80 rmnol) *Trade-mark and triethylamine (0.11 mL, 0.803 mmol) in tetrahydrofuran (8 mL) with stirring at room temperature for 3 hours. The product was isolated by flash chromatography and recrystallization from methylene chloride to yield 0.18g (6496) of the title compound: mp 110-114 ° C (dec.). ' H NMR (DMSOda) a 9.47 (s, 1 H), 8.65 (d, J = 1.5 Hz, 1 H), 8.35 (s, 1 H), _8.03 (dd, J = 1.5, 5 Hz, 1 H), 7.77-7.70 (m, 2H), 7.53 (dd, J = 2, 9 Hz, 1 H), 7.46 (d, _J = 8 Hz, 1 H), 7.22 (t, J = 8 Hz, 1 H), 7.00 (d, J = 7.5 Hz, 1 H), 6.88 (dd, J = 5, 8 Hz, 1 H), 3.07 (br s, 4H), 2.63 (br s, 4H), 2.29 (s, 3H), 2.14 (s, 3H). HRMS
m/e calculated for CzzH~5Ns0: 375.2054. Observed m/e: 375.2023.
Examele 32 1-(4-Methyl-1-piperazinvll-7-( 1-pyridotriazolol-naphthalene The title product from example 29 (0.219 g, 0.657 mmol) was dissolved in 5 9'0 sulfuric acid (1.5 mL) and chilled to 0°C. Sodium nitrite (0.048 g, 0.69 mmol) was dissolved in water (0.25 mL) and added dropwise with a water rinse (2 x 0.25 mL). The mixture was allowed to stir overnight. The reaction was poured onto ice and neutralized with 1 N NaOH. The aqueous mixture was extracted 3 times with methylene chloride and the combined organic layer was washed with saturated sodium bicarbonate and brine. The organic phase was dried through phase separating paper and concentrated to a brown foam. The foam was recrystallized from methanol to afford 0.124 g (5596) of the title product as tan crystals: mp 162-164°C. 'H NMR a 9.28 (d, J = 2 Hz, 1 H), 8.82 (dd, J = 1.5, 4.5 Hz, 1 H), 8.52 (dd, J = 1.5, 8.5 Hz, 1 H), 8.39 (dd, J = 2, 9 Hz, 1 H), 8.05 (d, J = 9 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.52-7.45 (m, 2H), 7.19 (d, J = 7.5 Hz, 1 H), 3.27 (br s, 4H), 2.80 (br s, 4H), 2.45 (s, 3H).
Analysis calculated for CZOHzoNe: C, 69.75; H, 5.85; N, 24.40. Found: C, 69.69; H, 5.72; N, 24.15.
Example 33 7-(Imidazol-2-ono-f4.5-blpvridin-1-yl)-1-(4-methyl-1-piperazinyl)naphthalene A mixture of the title product of example 29 (0.260 g, 0.78 mmol) and triethylamine (0.21 mL, 1.56 mmol) in methylene chloride (12 mL) was chilled to 0°C
and triphosgene (0.09 g, 0.30 mmol) was added all at once. The mixture became homogeneous and was stirred overnight at ambient temperature. Additional triphosgene (0.02 g, 0.07 mmol) was added and the mixture was stirred 4 hours more.
Saturated sodium bicarbonate was added and the reaction was stirred 30 minutes to decompose any unreacted triphosgene. The phases were separated and the organic SUBSTITUTE SHEET (RULE 26~
2I584~~
~0-layer was washed with brine and dried through phase separating paper. The solution was concentrated and flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with hom 6096 to 10096 methylene chloride/hexane was not productive.
Continued elution with a gradient of from 2 to 496 methanol/methylene chloride gave 0.032 g of an oil which was discarded. Further elution with a gradient of 4 to methanol/methylene chloride gave 0.23 g of crystalline solid product. The solid was triturated with methylene chloride and filtered to afford 0.079 g (2896) of the title product as a white powder: mp 260-262°C (dec.). 'H NMR (DMSOda) 6 11.44 (br s, 1H), 8.49 (d, J = 1.5 Hz, 1 H), 8.01 (d, J = 9 Hz, 1 H), 7.97 (dd, J = 1.5, 5 Hz, 1 H), 7.86 (dd, J
= 2, 9 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7.49-7.42 (m, 2H), 7.16-7.11 (m, 2H), 3.10 (br s, 4H), 2.58 (br s, 4H), 2.25 (s, 3H). HRMS m/e calculated for CZ, Hz,N50:
359.1742.
Observed m/e: 359.1705. Analysis calculated for Cz,H~,NsO ~ HzO: C, 68.46; H, 6.02;
N, 19.01. Found: C, 68.38; H, 5.47; N, 18.66.
Examcle 34 1-(4-Methyl-1-piperazinyl)-7-(3-(3.3-dimethylformamidino)-2-pyridylaminol-naphthalene To a solution of the title product of example 29 (0.453, 1.36 mmol) in dry dimethyl formamide (5 mL) was added dimethyl formamide dimethyl acetal (5 mL, 35.4 mmol). The resulting solution was refluxed 4 hours and allowed to stir at room temperature overnight. The solvent was removed in vacuo and the residue was flash chromatographed on silica gel (1 x 7 inches). Gradient elution with from 50 to of ethyl acetate / hexane then a gradient of from 1 to 696 ethanol/ethyl acetate gave 0.352 g (67 96) of the title product as a yellow foam which was suitable for further reaction. A sample was recrystallized from ether gave the bright yellow crystalline title product for analysis: mp 108-111 °C. ' H NMR d 9.00 (d, J = 2 Hz, 1 H), 8.03-7.97 (m, 2H), 7.73 (d, J = 9 Hz, 1 H), 7.53-7.42 (sym m, 2H), 7.23 (t, J = 8 Hz, 1 H), 7.05-6.98 (sym m, 2H), 6.69 (dd, J = 5, 7.5 Hz, 1 H), 3.24 (br s, 4H), 3.13 (br s, 6H), 2.80 (br s, 4H), 2.46 (s, 3H). Analysis calculated for C23HzsNe: C, 71.10; H, 7.26; N, 21.63.
Found: C, 71.16; H, 7.17; N, 21.59.
Example 35 7-(Imidazolo(4,5-blpyridin-1-yl)-1-(4-methyl-1 p~erazinyl?-naphthalene The title product of example 34 (0.25 g, 0.64 mmol) was slurried in toluene and a catalytic amount of para toluenesulfonic acid (a couple of crystals) was added. The SUBSTITUTE SHEET (RULE 26) ~1-mixture was refluxed 4 hours, cooled and concentrated. The residue was taken up in methylene chloride and washed with saturated sodium bicarbonate and brine;
then it was dried over calcium sulfate and concentrated to a yellow oil (0.165 g). The oil was further purified by recrystallization from ether to afford 0.057 g (26 96) of the title product as yellow crystals: mp 107-112 ° C; ' H NMR a 8.65 (d, J = 2 Hz, 1 H), 8.52-8.48 (m, 2H), 8.21 (dd, _J = 1.5, 8 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.87 (dd, J = 2, 8 Hz, 1 H), 7.64 (d, -J = 8 Hz, 1 H), 7.46 (t, J = 8 Hz, 1 ), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.20 (d, J = 7 Hz, 1 H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H). Analysis calculated for C~,Hz,NS~HzO:
C, 71.57; H, 6.29; N, 19.87. Found: C, 71.32; H, 6.32; N, 19.44.
Example 36 7-(Imidazolof4 5-blpyridin-1-yl)-1-(4-meth~rl-1-piperazinyll-naphthalene The title product of example 29 (0.217 g, 0.65 mmol) was dissolved in acetic acid (3 mL) and diethyl ethoxymethylenemalonate (0.138 mL, 0.68 mmol) was added.
The mixture was stirred at 55°C for 5 hours. The reaction was cooled and diethyl ethoxymethylenemalonate (0.04 mL, 0.2 mmol) was added. The reaction was heated to 100°C overnight. The solvent was removed in vacuo and the residue was taken up in chloroform and neutralized with ice cold saturated sodium bicarbonate and washed with brine. The organic layer was dried over calcium sulfate, concentrated and flash chromatographed on silica gel (1 x 2.5 inches). Elution with methylene chloride and then 296 methanol/0.0596 ammonium hydroxide/methylene chloride gave an unweighed forerun. Continued elution with 496 methanol/0.0596 ammonium hydroxide/methylene chloride gave a tan oil which crystallized upon scratching. The crystals were collected, rinsed with ether, and dried to afford 0.066 g, (3096) of the title compound:
mp 107-112°C; 'H NMR a 8.65 (d, J = 2 Hz, 1H), 8.52-8.48 (m, 2H), 8.21 (dd, J
= 1.5, 8 Hz, 1 H), _8.04 (d, J = 8.5 Hz, 1 H), 7.87 (dd, J = 2, 8 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7.46 (t, J = 8 Hz, 1 ), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.20 (d, J = 7 Hz, 1 H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H).
Example 37 7-(Benzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene To a slurry of 10 96 palladium on carbon (0.022 g) in ethanol (5 mL) was added the product of example 28 (0.091 g, 0.25 mmol in 25 mL of dioxane). Methanol (5 mL) was added and the mixture was hydrogenated at 50 psi for 6 hours. The reaction was SUBSTITUTE SHEET (RULE 26) 2'58457 filtered through Celite and concentrated to afford n residue which was used without purification.
The above residue was dissolved in acetic acid (1.5 mL) and diethyl ethoxymethylenemalonate (0.058 mL, 0.29 mmol) was added. The mixture was stirred at 95°C for 2 hours. The mixture was chilled to 0°C and neutralized with 1 N NaOH.
The mixture was extracted with methylene chloride and this organic layer was washed with brine, dried through phase separating paper, end concentrated for flash chromatography on silica gel (1 x 2 inches). 50 to 10096 ethyl acetate/hexene gradient elution was not productive. Continued elution with 1 and 296 ethanol/ethyl acetate gave an unweighed forerun. Further elution with a gradient of trorn 4 to 1596 ethanol/ethyl acetate gave 0.083 g of a brown oil. The oil was recrystallized from ether to yield 0.039 g (4796) of the title compound as tan crystals: mp 148-150°C. 'H NMR 6 8.35 (d, J =
2 Hz, 1 H), 8.25 (s, 1 H), 8.04 (d, J_ = 8.5 Hz, 1 H), 7.94 (sym m, 1 H), 7.69-7.60 (m, 3H), 7.52 (t, J = 8 Hz, 1 H), 7.38 (sym m, 2H), 7.24 (d, J = 7.5 Hz, 1 H), 3.19 (br s, 4H), 2.70 (br s, 4H), 2.40 (s, 3H). HRMS m/e calculated for C~iH~~N,: 342.1840. Observed m/e:
342.1863.
Example 38 7-(3-Hydroxy-3-meth~t-1-butynyl~-1-(4-methyl-1-Qiperazinyl)-naphthalene crtoluene sulfonate 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.285 g, 0.761 mmol), 3-hydroxy-3-methylbutyne (0.12 ml, 1.24 mmol), triethylamine (0.52 mL, 3.73 mmol), and bis (iriphenylphosphine) palladium chloride (0.03 g, 0.04 mmol) were combined in dry dimethyl formamide (3 mL) and heated to 70 to 80°C.
After 40 min the reaction was cooled and poured into 30 mL of 1 N aqueous lithium chloride and extracted with ether (3 x 15 mL). The combined ether layer was washed wish water and brine; then it was dried over magnesium sulfate and concentrated to an orange oil. The oil was purified by flash chromatography on silica gel (1 x 6 inches). Elution with a gradient of ethyl acetate and hexane followed by 100' ethyl acetate gave 0.15 g of orange oily product (6596). The oil was dissolved in ether (5 mL) and p-toluene sulfonic acid (0.093 g, 0.489 mmol in ether) was added. An orange solid formed which was collected, rinsed well with ether and ethyl acetate. Recrystallization from ethanol/ether gave 0.113 g (3096) of the title product as a dark orange solid; mp 194.5-195.5°C. "C
NMF~ (DMSO d6) a 147.46, 145.70, 137.86, 133.54, 128.99, 128.66, 128.17, 127.75, *Trade-mark WO 94/21619 ~ PCT/US94/01206 ,-126.90, 125.59, 125.53, 124.23, 120.07, 116.59, 96.66, 81.06, 63.78, 53.02, 42.33, 31.70, 20.80.
Example 39 7-(2-Ethylsulfonyl)ethenyl-1-(4-methyl-l~ipera2iny11-naphthalene (L) tartrate The title product was prepared following the procedure of example 1 from 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 2-ethylsulfonyl-1-chloroethane (0.11 g, 0.7 mmol), triethylamine (0.47 mL, 3.37 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in dimethyl formamide (10 mL), the reaction being carried out at reflux for 4 hours followed by stirring at ambient temperature overnight. The product was purified by flash chromatography on silica gel (1 x 4 inches). Elution with 50 and 7596 ethyl acetate/hexane gave recovered starting material (0.07 g, 2896). Continued elution with ethyl acetate and then 1096 methanol/ethyl acetate gave 0.06 g (2696) of product; 'H
NMR a 8.31 (d, J = 1 Hz, 1 H), 7.85-7.77 (m, 2H), 7.62-7.44 (m, 3H), 7.15 (dd, J = 1.3, 7.2 Hz. 1 H), 6.90 (d, J = 15.5 Hz, 1 H), 3.19-3.10 (m, 6H), 2.75 (m, 4H), 2.45 (s, 3H), 1.42 (t, J = 7.5 Hz, 3H). The (L) tartrate salt was formed in methanol with 1 equivalent of (L) tartaric acid. Concentration of the methanolic solution and recrystallization from ethyl acetate/ether gave 0.035 g of light yellow hygroscopic solid title product: mp 110 120°C. Analysis calculated for C,9H~,NzOzS~C,HaOe~2Hz0: C, 52.07; H, 6.46; 0, 5.27.
Found: C, 51.70; H, 5.89; N, 5.11.
Example 40 7-(4-Chlorobenzylo~)-1-(4-meth-1-piperazinyl)-naphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol), 4-chlorobenzyl bromide (1.27 g, 6.18 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) ~ and refluxed 4.5 hours. The mixture was cooled to room temperature, filtered and concentrated to a yellow solid. This material was recrystallized from ether to yield 1.28 g (720) of 7-(4-chlorobenzyloxy)-a-tetralone as a light yellow solid: mp 91-92°C.
Analysis calculated for C"H,5CIOz: C, 71.20; H, 5.27. Found: C, 71.22; H, 5.20.
The product of the above reaction (1.0 g, 3.49 mmol) was combined with N
methylpiperazine (1.25 mL, 11.27 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.52 mL, 4.74 mmol) in methylene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to ambient temperature and stirred 2.5 hours; then it was SUBSTITUTE SHEET (RULE 26) 2~58~57 quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The THF
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 1.22 g (9596) of 7-(4-chlorobenzyloxy)-t-(4-rnethyi-1-piperazinyl)~,4-dihydronaphthalene as a light yellow solid: mp 115-116.5°C. Analysis calculated for C~~H=,CIN~O: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.54; H, 6.56; N, 6.95.
The product of the above reaction (1.2 g) was combined wish 1096 palladium on carbon (0.62 g, predried) in dry toluene (50 ml_) and refluxed. After several hours of retlux, 0.5 g more catalyst was added and the reaction was furlher refluxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded an orange oil which was purified by flash chromatography on silica gel (1 x 4 inches). Elution with 50 96 ethyl acetate/hexane gave unweighed recovered starting material. Continued elution as above gave 0.54 g of 7-hydroxy-1-(4-methyl-1-piperazinyi)-naphthalene. Furlher elution with ethyl acetate gave the title product (0.06 g). The title product was recrystallized from ether to afford 0.033 g (2.796) of light yellow solid: mp 111.5-112°C. Analysis calculated for C~1H?~CIN~O: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.92; H, 6.27; N, 7.69.
Example 41 7-(3-Methytaminosulfonylphenyl)-1-~(4-methyt-1 pi~erazinyf)naphthalene 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-rnett~ylaminosulfonyl-1-bromobenzene (0.18 g, 0.72 mmol), triethylarnine (0.45 rnL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) were combined in DMF (12.5 mL) and heated to 110 to 110°C for 45 minutes. The reaction was cooled to room temperature and 1 N aqueous lithium chloride (20 mL) was added. The mixture was extracted with ether (2x). The combined organic layer was washed with 1 N lithium chloride and brine; Then it was dried over magnesium sulfate and concentrated to an orange oil. Flash chromatography on silica gel (1 x 6 inches) with an ethyl acetate/hexane gradient of from 50 to 75'j6 followed by continued elution with ethyl acetate and finally rnethanol/ethyl acetate 0.11 g (4296) of the title product. The sample was recrystallized *Trade-mark WO 94/21619 ~~ ~ PCT/US94/01206 from ethyl acetate for analysis: mp 147.5-148°C. Analysis calculated for Cz=HnN~O~S:
C, 66.81; H, 6.31; N, 10.62. Found: C, 66.32; H, 6.16; N, 10.41.
Example 42 7-(3-Methylsutfonylaminophenyl)-1-(4-meth5rl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylsulfonylamino-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours. The product was obtained in 3596 yield. A sample was obtained by recrystallization from ethyl acetate for analysis: mp 100-101 °C. Analysis calculated for CzzHz5N30~S~1.5 HBO: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89.
Example 43 7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.1 g, 0.27 mmol), benzoyl chloride (0.031 mL, 0.27 mmol) and bis (acetonitrile) palladium chloride (0.007 g, 0.027 mmol) were combined in chloroform (5 mL) and heated to 60 to 65°C for 15 minutes. The reaction was cooled to room temperature and saturated aqueous ammonium chloride (10 mL) and chloroform (10 mL) were added. Phases were separated and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to a milky oil. The oil was purified by flash chromatography on silica gel (1 x 6 inches), the product eluting with 596 methanol/ethyl acetate as a yellow oil (0.07 g, 7996). The oil was crystallized from ether to obtain a bright yellow solid: mp 124-124.5°C. Analysis calculated for CzzH~zN~O: C, 79.97; H, 6.71; N, 8.48. Found:
C, 79.74; H, 6.69; N, 8.46.
Example 44 7-(a-Hydroxybenzyl)-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 43 (0.121 g, 0.366 mmol) was dissolved in ethanol (3 mL) and sodium borohydride (0.025 g, 0.66 mmol) was added. The mixture was stirred 1 hour at ambient temperature, then it was concentrated at reduced pressure at 40°C. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated to a light yellow oil. The oil was purified by SUBSTITUTE SHEET (RULE 26) flash chromatography on silica gel (1 x 4 inches). Elution with 5096 ethyl acetatelhexane removed a fast moving component which was not identfied.
Continued elution with ethyl acetate gave 0.066 mg of the title product as a light tan oil which solidified. This solid was recrystallized from chloroform/ether to afford 0.033 mg (2796) of the title product as a light tan solid: mp 162.5-163°C. Analysis calculated for C~zHz,N~O~0.25 HzO: C, 78.42; H, 7.33; N, 8.31. Found: C, 78.52; H, 7.06; N, 8.31.
Example 45 7-(Diahenylhydroxymethyll-1-(4-methyl-1-aiaerazinvl)-naphthalene The title product of example 43 (0.072 g, 0.218 mmol) was dissolved in dry THF
(10 mL) and chilled to 0°C. Phenyl magnesium bromide (3 M in ether, 0.08 mL, 0.24 mmol) was added dropwise. The mixture fumed greenish and then returned to a yellow color. The reaction was allowed to warm to room temperature for 30 minutes and then refluxed for 45 minutes. Additional phenyl magnesium bromide (0.1 mL, 0.26 mmol) was added and the mixture was refluxed 1 hour more. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to a light yellow oil. The product was purified by silica gel flash chromatography (1 x 6 inches).
Elution with 5096 ethyl acetate/hexane followed by ethyl acetate gave 0.082 g (9296) of the title product. A sample was recrystallized from chloroform/ether for analysis: mp 217.5-218.5°C. Analysis calculated for CzeH~eN~O~0.5 HBO: C, 80.54; H, 7.00; N, 6.71.
Found: C, 80.47; H, 6.63; N, 6.78.
Example 46 7-(p-Biphenyll-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 4-bromobiphenyl (0.17 g, 0.73 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1 hour at 100 to 115°C.
The product obtained was 0.14 g (56°k) in yield. A sample was obtained by recrystallization from ether/hexane for analysis: mp 138.5-139.5°C. Analysis calculated for C~,H~NZ: C, 85.67; H, 6.92; N, 7.40. Found: C, 85.12; H, 6.97; N, 7.44.
SUBSTITUTE SHEET (RULE 26) ~47-Example 47 7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1 piperazinyl)-naphthalene The title product was prepared following the procedure of example 41 from 7 trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3 methoxycarbonyl-1-bromobenzene (0.16 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours at 120 to 130°C. The product obtained was 0.15 g (6396) in yield as an oil which was converted to a hydrochloride salt with HCI gas in ether. The solid was collected under a nitrogen atmosphere and recrystallized from chloroform/ether for analysis:
mp 201-203°C; "C NMR d 167.05, 147.37, 141.78, 137.80, 134.08, 131.87, 130.89, 129.57, 129.07, 128.63, 128.47, 126.28, 125.76, 125.02, 120.59, 116.85, 54.30, 52.33, 49.75, 43.70.
Example 48 7-l3-Fluorophenvl)-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-fluoro-1-bromobenzene (0.13 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 2 hours at 120 to 130°C.
The product obtained was 0.13 g (5996) in yield. A sample was obtained by recrystallization from ether/hexane for analysis: mp 116-116.5°C. Analysis calculated for C2zH~,FNz: C, 79.49; H, 6.37; N, 8.43. Found: C, 79.07; H, 6.46; N, 8.66.
Example 49 7-(BenzyIoxY)-1-(4-meth~rl-1-piperazinyl)-naphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol), benzyl bromide (0.80 mL. 6.73 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed 22 hours. The mixture was cooled to room temperature, filtered and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The phases were separated and the organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated to a pale yellow solid. The material was recrystallized from ether/hexane SUBSTITUTE SHEET (RULE 26) to yield 0.80 g (51%) of 7-benzyloxy-v-tetrnlone as a cream solid: mp 84-84.5°C.
Analysis calculated for C"ti,a0i: C, 80.93; H, 6.39. Found: C, 80.39; H, 6.11.
The product of the above reaction (0.75 g, 2.97 mmol) was combined with N
methylpiperazine (1.06 mL, 9.56 mmol) (n dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.44 mL, 4.01 mmol) in methyiene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to ambient temperature end stirred overnight; then it was quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The TI-F
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2 x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 0.93 g (9496) of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene as an orange oil which was suitable for use without further purification. 'H NMR d 7.48-7.28 (m, 5H), 7.08-7.05 (m, 2H), 6.79 (dd, J =
2.7, 8.2 Hz, 1 H), 5.30 (t, ~ = 4.7 Hz), 5.10 (s, 2H), 2.84 (br s, 4H), 2.64-2.50 (t, J_ =
7.5 t-iz t 5 overlapping wish br s centered at 6 2.54, 6H total), 2.37 (s, 3H), 2.25-2.17 (m, 2H).
The product of the above reaction (0.93 g, 2.78 mmol) was combined with 1096 palladium on carbon (0.65 g, predried) in dry toluene (30 mL) and reRuxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded a yellow oil which was purified by (lash chromatography on silica gel (1 x 4 inches). Elution with 5096 ethyl acetate/hexane gave unweighed recovered starting material. Continued elution with 7596 ethyl acetate/hexane gave 0.18 g of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-naptothalene es a colorless oil. Recrystallization from ether gave 0.09 g (9.896) of the tile product as a white solid: mp 81.5-82.5°C. Analysis calculated for C7,li"N,O: C, 79.48; t-1, 7.28; N, 8.43. Found: C, 79.29; H, 7.41; N, 8.30. Further elution with ethyl acetate gave 0.47 g of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene.
Example 50 7-(3,4-Dichlorobenzyloxy~i-1-(4-methyl-1_piperazinyll-naphthalene 7-Hydroxy-o-tetralone (1.0 g, 6.17 mmol), 3,4-dichlorobenzyl bromide (t .48, G.18 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed 21.5 hours. The mixture was cooled to room temperature, filtered and concentrated at reduced pressure. The reside was partitioned between ethyl acetate and 1 N sodium hydroxide. The phases were separated and the organic layer was *Trade-mark washed with water and brine; then it was dried over magnesium sulfate and concentrated to a pale yellow solid. This material was recrystallized from ether to yield t .04 g (5396) of 7-(3,4-dichlorobenzyfoxy-a-tetralone as a fluffy white solid: mp 122.6-123°C. Analysis calculated for C"H"CItO~: C, 63.57; ti, 4.39. Found: C, 63.36; H, 4.21.
The product of the above reaction (0.90 g, 2.8 mmol) was combined with N-methylpiperazine (1.0 mL, 9.01 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to arnbient temperature and stirred overnight; then it was quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The THF
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 1.08 g (9696) of 7-(3,4-dichlorobenzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene as a yellow oil which was suitable for use without further purification. ' H NMR ~ 7.55 (d, J=2 Hz, 1 H), 7.45 (d, J=8.2 Hz, 1 H), 7.29-7.25 (m, _1 H), 7.07 (d, J=8.2 Hz, 1 H), 7.00 (d, J=2.7 Hz, 1 H), 6.75 (dd, J=2.7, 8.2 Hz, 1 H), 5.30 (t, J=4.7 Hz, 1 H), 5.05 (s, 2H), 2.80 (br s, 4H), 2.63-2.43 (m, 6H), 2.36 (s, 3H), 2.30-2.16 (m, 2H).
The product of the above reaction (1.08 g, 2.68 mmol) was combined with 1096 palladium on carbon (0.65 g, predried) in dry toluene (30 mL) and refiuxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded a brown oil which was purified by (lash chromatography on silica gel (1 x 4 inches). Elution with 7596 elhyi acetate/hexane gave an unweighted forerun. Continued elution with ethyl acetate gave 0.22 g of light yellow solid. Recrystallization from ether gave 0.148 g (1496) of the title product as a straw colored solid: mp 113-114°C. Analysis calculated for C"H?iCI,N~
O: C, 65.84; H, 5.53; N, 6.98. Found: C, 66.18; H, 5.63; N, 7.02.
Example 51 7-(4-Tritluoromethylbenzyloxy~-~4-methyl-1-piperazinyll-naphthalene To a mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.20 g, 0.83 mmol), triphenylphosphine (0.32'g, 1.22 mmol), and 4-tritluoromethylbenzyl alcohol (0.17 mL, 1.26 mmol) in dry THF (4 mL) was added diethyl azodicarboxylate in Tt-iF (1 *Trade-mark mL). The mixture was stirred ovemlght at ambient temperature; then it was concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was washed with water and brine;
then it was dried over magnesium sulfate and concentrated onto silica gel for flash chromatographic purification (1 x 6 inches). Elution with 7596 ethyl acetate/hexane gave 0.24 g (7296) of the title compound as a nearly colorless oil. The oil was treated with HCI in ether to form the hydrochloride salt (0.23 g) which was recrystallized from chloroform/ether to give 0.14 g of a white solid thereof: mp 205-206°C.
Analysis calculated for C~~Hz~F~N~O~HCI~0.25 HzO: C, 62.58; H,. 5.59; N, 6.35. Found:
C, 62.59; H, 5.63; N, 6.40.
Example 52 7-Benzoylo~-1-(4-methyl-1-pJ~erazinyl~-naphthalene A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a second equivalent of benzoyl chloride was added with continued stirring overnight. The reaction was diluted with ethyl acetate and the phases were separated.
The organic layer was washed with 1 N sodium hydroxide, water and brine; then it was dried over magnesium sulfate and concentrated to an oil which solidified (0.065 g, 6996). A sample recrystallized from ether/hexane as a light pink solid was submitted for analysis: mp 82-82.5°C. Analysis calculated for C~=H==NzO~~0.25 HBO: C, 75.30;
H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Example 53 7-(4-Chlorobenzovloxy,)-1-(4-methyl-1-piperazinyl l-naphthalene The title product was obtained following the procedure of example 30 from 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and 4-chlorobenzoyi chloride (0.035 mL, 0.275 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) with a second equivalent of 4-chlorobenzoyl chloride added after several hours of stirring at room temperature. The title product was obtained in a yield of 0.058 g (5796) after recrystallization from ether/hexane: mp 110-111 °C. Analysis calculated for CzzHz,CIN~O~: C, 69.38; H, 5.56; N, 7.36. Found:
C, 69.31; H, 5.61; N, 7.35.
SUBSTITUTE SHEET (RULE 26) ~~1'S8 ~~'~
Example 54 7-(3-Chlorobenzyloxvl-1-(4-methyl-1-picen3zinvl)-naphthalene A mixture of 3-chlorobenzyi bromide (1.27 g, 6.18 mmol), 7-hydroxy-a-tetralone (1.0 g, 6.17 mmol), and potassium carbonate (1.7 g, 12.3 mmol) in acetone (30 mL) was refluxed overnight. The reaction was cooled, flttered, and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to a yellow solid. Reaystallization from ether/hexane gave 0.87 g (4996) of 7-(3-chlorobenzyloxy)-a-tetralone as a cream colored solid: mp 77-78°C. Analysis calculated for C"H,5CI0=: C, 71.20; H, 5.27. Found:
C, 71.25; H, 5.09.
A solution of 7-(3-chlorobenzyloxy)-a-tetralone (0.8 g, 2.79 mmol) and 1-methylpiperazine (1.0 mL, 4.0 mmol) in dry THF (50 mL) was cooled to -78°C and treated with titanium tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL).
The reaction was stirred 10 minutes at -78°C, then warmed to room temperature and stirred overnight. The mixture was quenched with 50 mL of 5 N ammonia and extracted with ethyl acetate (2x). This combined organic layer was dried over magnesium sulfate and concentrated to a colorless oil (0.98 g, 9596). This enamine was used directly in the next step.
A mixture of the enamine (1.0 g, 2.71 mmol) and sulfur (1.1 g, 34.31 mmol) in decalin (10 mL) was lowered into an oil bath preheated to 170°C. The mixture was stirred 20 minutes; then it was cooled and the decalin was removed by short path distillation. The residue was dissolved in carbon disulfide and flash chromatographed on silica gel (1 x 6 inches). Elution with carbon disulfide removed residual sulfur.
Continued elution with 5096 ethyl acetate/hexane and finally with pure ethyl acetate gave 0.09 g of brown oil. The product was combined with 0.03 g of product from a previous preparation and treated with decolorizing carbon in ether. Recrystallization from hexane gave 0.026 g (2.696) of the title product as a light yellow solid: mp 67.5-68°C.
Analysis calculated for Cz~Hz,CIN20: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.95; H, 6.32; N, 7.47.
SUBSTITUTE SHEET (RULE 26) temple b5 7-Tritluorometh~,risulfonyloxY-1-(4-methyf-1-eiperaziny~l ~-naphthalene 7-Hydroxy-1-(4-methyl-1-piperazlnyl)-naphthalene (4.1 g, 16.9 mmol) and triethylarnine (12.8 mL, 91.8 mmol) were dissolved in methytene chloride (150 mL) and cooled to -78°C. Triflic anhydride (3.04 mh 18.1 mmol) was added via syringe and tl~e reaction was warmed to room temperature and stirred overnight. The reaction was again chilled to -78°C and additional triflic anhydride (1 ml-) and triethyfamine (2 mL) were added but after 2 hours stirring nt ambient temperature, no further reaction occurred. Saturated ammonium chloride was added and the mixture was concentrated.
The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to a brown oil which was purified by silica gel flash chromatography (2 x 6 inches). Elution with 7596 ethyl acetate/hexane gave 4.49 g (7196) of the title product as a light brown solid: mp 7U-71 °C. Analysis calculated for C,aH"F~NIO,S: C, 51.33; H, 4.58; N, 7.48.
Found: C, 51.35; H, 4.46; N, 7.49.
Example 56 7-8enzamido-1-(4-methyl-1-piperezinvll-naphthalene 7-Benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene (0.795 g, 2.29 rnmol, an intermediate from Exarnple 1), freshly distilled dicyclopentadiene (70°C at 1 Torr, 0.909 g, 6.87 mmol), and 1096 palladium on carbon (0.2 g, predried) were combined in xylene (25 mt_)~ and retluxed 4 hours. The mixture was cooled and additional palladium on carbon (0.3 g) was added. The reaction was refluxed vigorously and xyfene was distilled out of the reaction until the volume of the reaction was reduced to about 10 mL. The reaction was retluxed overnight, cooled, and filtered *
throughCelite. The filtrate was concentrated on silica gel and flash chromatographed on silica gel. Gradient elution with from 5096 to 10096 ethyl acetate/hexane gave a forerun containing an unweighed amount of 7-benzamido-o-tetralone. Continued gradient elution with 29'° to 1096 methanol/ethyl acetate gave 0.49 g (6296) of the title product: mp 172-173.5°C.
Alternatively, (2,2,2) bicyclooctene was used in place of dicyclopentadiene in the above dehydrogenation reaction to produce the title product in 6696 yield after recrystallization horn ethyl acetate/hexane.
*Trade-mark ~~,1'~
Example 57 7-Amino-1-(1-methvl~-piperidinvll-naphthalene The following reaction was run in two side by side reactions and the crude products were combined for work up and purification. A mechanically stirred solution of 8-bromo-2-(dibenzylamino)-naphthalene (10.0 g, 24.9 mmol from Preparation 4) in tetrahydrofuran (200 mL) was cooled to -95°C (hexane/liquid nitrogen) and butyllithium (10.39 mL, 24.9 mmol, 2.4 M) was added dropwise. The orange solution was stirred 7 min, then 1-methyl-4-piperidone (2.82 g, 24.9 mmol) was added dropwise over minutes with a 10 mL tetrahydrofuran rinse. The orange color faded while stirring was continued 20 minutes at -100°C. The reaction was allowed to warm to room temperature and quenched with water. The solvent was removed and the residue was partitioned between methylene chloride and water (at this point the two reactions were combined). The phases were separated and the organic layer was washed with brine, dried, and concentrated onto silica gel. Flash chromatography (4 x 4 inches silica gel) proceeded as follows: methylene chloride (1 L) and 296 methanol / methylene chloride (1.6 L) unweighed white solid 7-dibenzylaminonaphthalene; 1596 methanol /
methylene chloride (1 L), 2596 methanol / methylene chloride (1 L) and 3096 methanol /
methylene chloride / 0.296 ammonium hydroxide (4 L) product contaminated with water. The combined eluents were concentrated and redissolved in methylene chloride. The solution was dried and concentrated to afford 15.09 g (6996) of 7-dibenzylamino-1-(4-hydroxy-1-methyl-4-piperidinyl)-naphthalene as a light tan foam. A sample recrystallized from ethyl acetate had mp 173-174°C. Analysis calculated for C3°H3~N~0: C, 82.53;
H, 7.39; N, 6.42. Found: C, 82.42; H, 7.44; N, 6.38.
The product from the above reaction (15.0 g, 34.38 mmol), p-loluenesulfonic acid (7.85 g, 41.26 mmol) and toluene (500 mL) were combined and refluxed 4 hours with azeotropic removal of water. The mixture was allowed to stand at room temperature 48 hours, then additional p-toluenesulfonic acid (1.4 g) was added and the mixture was refluxed 5 hours more. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. This organic phase was washed with 1 N sodium hydroxide (2 x) and brine, then it was dried over calcium sulfate and concentrated to give 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphthalene as a brown oil which crystallized on standing (13.8 g, 9696).
This material was suitable for use in the next reaction. A sample recrystallized from ethyl SUBSTITUTE SHEET (RULE 26) ry W0 94/21619 PCT/US94/01206 acetate had mp 124-126°C. The analytical sample was recrystallized from isopropanol.
Analysis calculated for C,°H,°N~ ~ 0.5 HsO: C, 84.27; H, 7.31;
N, 6.69. Found: C, 83.85; H, 6.97; N, 6.39.
A mixture of 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphtha lene (2.85 g, 6.81 mmol) and palladium hydroxide (2096 on carbon, 2.06 g) in glacial acetic acid (60 mL) was hydrogenated 22 hours (starting pressure approximately psi). Additional palladium hydroxide (1 g) was added and hydrogenation was continued 13 hours more. The reaction was filtered through celite. The filtrate was neutralized with 4 N sodium hydroxide and extracted with methylene chloride.
This organic phase was washed with brine, dried and concentrated to 1.3 g of brown oil.
Crystallization from isopropanol gave 0.544 g (3396) of 7-amino-1-(1-methyl-4-piperidinyl)-naphthalene as light brown crystals. mp 169.5-171 ° C.
Analysis calculated for C,eH~°N~: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.14; H, 8.42; N, 11.52.
Example 58 7-(3-vitro-2-pyridvlamino,~-1-(1-methyl-4-piperidinyl)-naphthalene A mixture of the product from Example 57 (0.338 g, 1.4 mmol), 2-chloro-3-nitropyridine (0.446 g, 2.81 mmol), and 4-dimethylami~opyridine (0.172 g, 1.4 mmol) in dimethylformamide (6 mL) was refluxed 5 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1 N sodium hydroxide and brine, then it was concentrated onto silica gel and flash chromatographed (1 x 4 inches silica gel). The elution proceeded as follows: 7596 methylene chloride / hexane (175 mL) nil; methylene chloride (250 mL) unweighed excess 2-chloro-3-nitropyridine; 296 methanol / methylene chloride (200 mL) nil, (550 mL) 0.373 g of crude product contaminated with 4-dimethylamino-pyridine.
This material was triturated with ether and filtered to give 0.17 g of title product as orange crystals. 'H NMR d 10.34 (br s, 1 H), 8.59 (dd, J = 2, 8.5 Hz, 1 H), 8.54-8.50 (m, 2 H), 7.88 (d, J = 9 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.45 7.41 (m, 2 H), 6.89 (dd, J = 4.5, 8.5 Hz, 1 H), 3.27 (tt, J = 4, 11.5 Hz, 1 H), 3.11 (long range coupled d, J = 11.5 Hz, 1 H), 2.41 (s, 3 H), 2.27 (dt, J = 2.5, 11.5 Hz, 2 H), 2.09 1.89 (m, 4 H).
SUBSTIT1JTE SHEET (RULE 26) WO 94/21619 ~~ PCT/US94/01206 Example 59 7-(Imidazolof4 5-b)pyridin-1-yl)-1-(1-methyl-4-piperidinvl)-naphthalene A mixture of the product from Example 58 (0.18 g, 0.5 mmol) and 10% palladium on carbon (0.04 g) in ethanol (35 mL) and ethyl acetate (15 mL) was hydrogenated at 45 psi for 4 hours. The mixture was filtered through celite and concentrated to give 7-(3-amino-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene which was suitable for further reaction; ' H NMR d 8.07 (d, J = 2 Hz, 1 H), 7.89 (dd, J = 1.5, 5 Hz, 1 H), 7.79 (d, J = 9 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45 (dd, J = 2, 9 Hz, 1 H), 7.36-7.26 (m, 2 H with CHCh from NMR solvent overlapping), 7.07 (dd, J = 1.5, 7.5 Hz, 1 H), 6.82 (dd, J = 5, 7.5 Hz, 1 H), 6.51 (br s, 1 H), 3.49 (br s, 2 H), 3.18 (tt, J = 4, 12 Hz, 1 H), 3.03 (long range coupled d, J = 13.5 Hz, 2 H), 2.39 (s, 3 H), 2.23 (dt, J =
2.5, 11.5 Hz, 2 H), 2.08-1.87 (m, 4 H). HRMS m/e calculated for C~,H=,N,: 332.1996. Observed m/e 332.2003.
The product from the above reaction and ethoxymethylenemalononitrile (0.079 g, 0.646 mmol) were combined in glacial acetic acid (7 mL) were refluxed 4 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1 N sodium hydroxide and brine, then it was dried and concentrated. This residue was flash chromatographed on silica gel (1 x 3.5 inches). Gradient elution with from 5096 ethyl acetate / hexane to pure ethyl acetate and then with from 2% to 596 methanol / ethyl acetate gave no product.
Continued elution with from 15% to 4096 methanol / ethyl acetate gave a tan foam product. Treatment with charcoal in methylene chloride, filtration and concentration gave 0.155 g of product. Recrystallization from ethyl acetate gave 0.04 g (2396) of the title compound as off white crystals. mp 118-120°C. Analysis calculated for C~ZH?~N,:
C, 77.16; H, 6.48; N, 16.36. Found: C, 76.99, H, 6.45; N, 16.27.
Example 60 7-(4-Chlorobenzamido-1-(1-methyl-4-piperidinyl)-naphthalene The product from Example 57 (0.202 g, 0.845 mmol), triethylamine (0.124 mL, 0.93 mmol) and 4-chlorobenzoyl chloride (0.118 mL, 0.93 mmol) were combined in acetonitrile (10 mL) at 0°C. The mixture was allowed to come to room temperature and stir overnight. The reaction was chilled back to 0°C and a second equivalent of acid chloride and triethylamine were added. The mixture was heated to 90°C
overnight.
The solvent was removed at reduced pressure and the residue was taken up in SUBSTITUTE SHEET (RULE 2fi) methylene chloride. The organic phase was washed with brine, dried, concentrated onto silica gei and flash chromatographed (0.5 x 3.5 inches). Elution proceeded as follows: methylene chloride then gradient elution with from 2% to 4% methanol /
methylene chloride was unproductive. Continued elution with from 4% to 696 methanol / methylene chloride gave 0.214 g of white foam. Recrystallization from chloroform /
ether gave 0.115 g of the title compound as tan crystals. mp 162-164°C.
The compound was converted to its hydrochloride salt with HCI in ether. Analysis calculated for C"Hz,CINzO ~ HCI: C, 66.51; H, 5.82; N, 6.74. Found: C, 66.12;
H, 5.76; N, 6.41.
Example 61 7-Amino-1-(1-methyl-3-~iperidinvl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (9.75 g, 24.3 mmol product of Preparation 4) in tetrahydrofuran (270 mL) was cooled to -78°C and butyllithium (9.72 mL, 24.4 mmol, 2.4 M) was added dropwise. The orange solution was stirred 20 minutes, then 1-t-butoxycarbonyl-3-piperidone (4.84 g, 24.3 mmol dissolved in 5 mL
tetrahydrofuran ) was added dropwise with a 5 mL tetrahydrofuran rinse. The reaction was stirred 30 minutes at -78°C, then allowed to warm to room temperature and stir 1 hour. The solvent was removed and the residue was partitioned between methylene chloride and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate, and concentrated onto silica gel. Flash chromatography (3 x 3 inches silica gel) proceeded as follows: 5% ethyl acetate /
hexane (1.4 L) and 1096 ethyl acetate / hexane (1 L) unweighed white solid 7-dibenzylaminonaphthalene; 25%ethyl acetate / hexane (1.5 L) 6.46 g (51%) of 7-dibenzylamino-1-(1-t-butoxycarbonyl-3-hydroxy-3-piperidinyl)-na phthalene which was suitable for use without further purification. A sample recrystallized from ethyl acetate / hexane had mp 145-147°C.
The product of the above reaction (1.0 g, 1.9 mmol) and dry benzene (20 mL) were chilled to 0°C and Burgess salt (0.958 g, 4.02 mmol) was added.
The mixture was heated to 55°C for 2 hours, then allowed to stir at ambient temperature overnight.
Water was added and after stirring an additional 15 minutes, the phases were separated. The organic layer was washed with brine and the combined aqueous washes were back extracted with ethyl acetate. The combined organic layer was dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1 x 3 SUBSf ITUTE SHEET (RULE 26) inches). Elution 2% to 496 ethyl acetnta / hexane gave 0.68 g (70%) of a mixture of both possible dehydration products (7-dibenzylamino-1-(1-t-butoxycarbonyl-1,4,5,6-tetrahydropyrid~-yl)-naphthalene and 7-dibenzylamino-1-(1-t-butoxycarbonyi-1,2.5,6-tetrahydropyrid-3-yt)-naphthalene). The products could be separated by careful chromatography but were carried as a mixture in this sequence.
A slurry o1 lithium aluminunn hydride (0.172 g, 4.52 mmol) in tetrahydrofuran (20 mL) was chilled to 0°C and the product of the above reaction (0.568 g, 1.13 mmol in 5 mL tetrahydrofuran) was added with a tetrahydrofuran rinse (2 x 2.5 mL). The mixture was refluxed 4 hours, chilled to O°C and quenched with sodium sulfate decahydrate.
t O The reaction was filtered and the filter cake was rinsed well with methyfene chloride.
The filtrate was concentrated and the residue was taken up in methyfene chloride. This organic phase was washed with water and brine, dried and concentrated to give 0.455 g of a 2:1 mixture of oleTin products (7-dibenzylamino-1-(1-methyl-1,4,5,6-tetrahydro-pyrid-3-yl)-naphthalene and 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-naphthalene) as judged by integration of the methyl signals in the NMR
spectrum (2.52 ppm - major and 2.27 ppm - minor). This material was carried on without further purification or characterization.
The product mixture from the above reaction (4.0 g, 9.56 mmol) and palladium hydroxide (2096 on carbon, 3.75 g) in glacial acetic acid (141 mL) and ethanol (141 mL) was hydrogenated 4 hours (starting pressure approximately 50 psi). Additional palladium hydroxide (0.8 g) was added and hydrogenation was continued 5 hours more. The reaction was filtered through Celite. The filtrate was neutralized with 4 N
sodium hydroxide and extracted with methylene chloride. This organic phase was washed with brine, dried, concentrated onto silica gel and flash cloromatographed (2 x 3 inches). Elution proceeded as follows: 7596 ethyl acetate / hexane (400 mL), ethyl acetate (400 mL), and 296 methanol / ethyl acetate (400 mL), nil; 296 triethylamine / 596 methanol / ethyl acetate (400 mL), 0.45 g of an unidentified brown loam; 296 triethylamine / 6'j6 methanol / ethyl acetate (500 roL) and 396 triethylamine methanol / ethyl acetate (500 mL), 1.35 g (549'0) of brown foam title product.
Further purification by treatment with activated charcoal followed by trituration in ether gave 0.362 g of the title compound as pink crystals which had mp 117-120°C.
HRMS rn/e calculated for C,aH7°N~: 240.1622. Observed m/e 240.1623. Analysis calculated for C,eH,°N~: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.02; H, 8.22; N, 11.10.
*Trade-mark 21584~'~
Example 62 7-(3-Nitro-2-nyridylamino)-1-( 1-methyl-oiperidinvl)-nachthalene A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from Example 61 ), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL, 1.05 mmol) in dimethylfortnamide (10 mL) was refluxed overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride.
The organic phase was washed with 0.5 N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 3 Inches). Elution proceeded as follows: 5096 ethyl acetate / hexane (500 mL) unweighed forrun;
ethyl acetate / hexane (400 mL) and ethyl acetate (100 mL) 0.151 g (5196) of red oil product. A sample crystallized from ether gave the title compound as red crystals. mp 107-108°C. Analysis calculated for C~,H~~N,Oz: C, 69.59; H, 6.12; N, 15.46. Found:
C, 69.30; H, 5.91; N, 14.92.
~.-xamole 63 7-~(Imidazolof4.5-blpyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene A mixture of the 7-(3-vitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene (0.12 g, 0.33 mmol from Example 62) and t 096 palladium on carbon (0.03 g) in ethanol (10 mL) and methanol (20 mL) was hydrogenated at 50 psi for 4 hours. The reaction was filtered through celite and concentrated to the brown oil product (7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene) which was suitable for use without further purification. ' H NMR a 7.89-7.83 (m, 2 H), 7.78 (d, J = 9 Hz, 1 H), 7.64 (dd, J
= 2, 9 Hz, 2 H), 7.33-7.23 (m, 2 H, partially obscurred by NMR solvent), 7.02 (dd, J =
1.5, 7.5 Hz, 1 H), 6.78 (dd, J = 5, 7.5 Hz, 1 H), 6.55 (br s, 1 H), 3.54 (long range coupled t, J = 11.5 Hz, 1 H), 3.18 (long range coupled dd, J = 1.5, 11 Hz, 1 H), 2.99 (long range coupled d, J = 10.5 Hz, 1 H), 2.34 (s, 3 H), 2.17-1.97 (m, 3 H), 1.94-1.81 (sym m, 2 H), 1.69-1.51 (m, 1 H). HRMS m/e calculated for CI,H~,N,: m/e 332.2000.
Observed m/e 332.2002.
A mixture of 7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene (0.104 g, 0.313 mmol) and ethoxymethylenemalononitrile (0.056 g, 0.459 mmol) in glacial acetic acid (5 mL) was refluxed 6 hours. The reaction was cooled, neutralized with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows: 5096 ethyl SUBSTITUTE SHEET (RULE 26) acetate / hexane (200 mL), 7596 ethyl acetate / hexane (200 mL), ethyl acetate (200 mL) and 196 methanol / 196 triethylamine / ethyl acetate (300 mL) nil; 396 methanol / 396 triethylamine / ethyl acetate (300 mL) 0.076 g (70 96) of 7-(imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene as a faint green oil. The product was characterized as its HCI salt which crystallized from isopropanol. mp >
250° C. ' H
NMR (DSO) d 9.30 (br s, 1 H), 8.51 (d, J = 5 Hz, 1 H), 8.40 (s, 1 H), 8.32 (d, J = 7.5 Hz, 1 H), 8.11 (d, J = 9 Hz, 1 H), 7.94 (d, J = 8 Hz, 1 H), 7.73 (dd, J = 2, 9 Hz, 1 H), 7.68-7.53 (m, 3 H), 3.77 (long range coupled t, J = 11.5 Hz, 1 H), 3.62 (br t, J = 10.5 Hz, 2 H), 3.22 (t, J = 12.5 Hz, 1 H), 3.07 (sym m, 1 H), 2.87 (s, 3 H), 2.23-2.05 (m, 2 H), 2.04-1.78 (sym m, 2 H). Analysis calculated for CzZH~~N, ~ 2HCI ~ HBO: C, 60.97; H, 6.05; N, 12.93. Found: C, 60.89; H, 6.00; N, 12.61.
ExamJ~le 64 7-Benzamido-1-(1-methyl-3-piperidinyl)-naphthalene A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.203 g, 0.845 mmol, product of example 61 ) and triethylamine (0.141 mL, 1.01 mmol) in tetrahydrofuran (5 mL) was chilled to 0°C and benzoyl chloride (0.118 mL, 1.01 mmol) was added. The mixture was warmed to room temperature and stirred overnight.
The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was extracted with 0.5 N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2 inches).
Elution proceeded as follows: 5096 ethyl acetate / hexane (225 mL), 7596 ethyl acetate / hexane (150 mL) nil; 7596 ethyl acetate / hexane (400 mL) and ethyl acetate (200 mL) 0.198 g of pink foam. This product was converted to an HCI salt in methanol, treated with activated carbon, and filtered. The filtrate was concentrated and triturated with ether to give 0.091 g (3196) of the title compound as an amorphous solid with a melting range of 140-170°C. 'H NMR (DMSO da) a 10.59 (s, 1 H), 10.34 (br s, 1 H), 8.73 (s, 1 H), 8.06 (d, J = 7 Hz, 2 H), 7.94 (distorted t, J = 10 Hz, 2 H), 7.82 (d, J =
7 Hz, 1 H), 7.63-7.53 (m, 3 H), 7.47-7.39 (m, 2 H), 3.78 (br t, J = 12 Hz, 1 H), 3.56 (br t, J = 11 Hz, 2 H), 3.05 (br s, 1 H), 2.83 (br s, 3 H), 2.15-1.97 (m, 2 H), 1.71 (br s, 1 H). HRMS m/e calculated for Cz,H~4Nz0: m/e 344.1883. Observed m/e 344.1886.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 215 8 4 ~ ~ pCT~S94101206 Example 65 7 (4-Chlorobenzamido) 1-(4-methoxyethyl-1-pi~erazinvl)-naphthalene A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol, product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164 mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile (7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced pressure. The residue was taken up in methylene chloride and washed with 1 N sodium hydroxide and brine, dried, concentrated , onto silica gel and flash chromatographed (1 x 2.5 inches). Elution proceeded as follows: 5096 ethyl acetate / hexane (100 mL) and 7596 ethyl acetate / hexane (100 mL), nil; 7596 ethyl acetate /
hexane (100 mL) and ethyl acetate (150 mL), 0.121 g (6996) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene as an oil. This oil was converted to the HCI
salt from an ether solution. An amorphous white powder hydrochloride salt of the title compound was obtained. mp 134-148°C. 'H NMR a 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J = 9 Hz, 3 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.55-7.43 (m, 3H),7.36(t,J=8Hz,1 H),7.11 (dd,J= 1,7.5 Hz, 1 H),3.57(t,J=5.5Hz,2H), 3.38 (s, 3 H), 3.19 (br s, 4 H), 2.83 (br s, 4 H), 2.70 (t, J = 5.5 Hz, 2 H).
Analysis calculated for C~,H~eCIN,O=~2HCI~l.5Hz0: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Example 66 7 (4 -Chlorobenzamido)-1-(4-propel-1-piperazinyl)-naphthalene A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol, the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride (0.103 g, 1.64 mmol) in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient temperature for 20 hours. The solvent was removed at reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Phases were separated and the organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1 x 3 inches). Elution proceeded as follows: ethyl acetate (50 mL) unweighed forrun;
ethyl acetate (250 mL) 0.164 g of yellow foam. The foam was triturated with pentane and 0.079 g (2896) of the title compound was collected as a white solid. mp 132°C. Analysis calculated for C"HsaCIN,O: C, 70.66; H, 6.42; N, 10.30.
Found: C, 70.91; H, 6.66; N, 10.50.
SUBSTITUTE SHEET (RULE 26) -61 _ Example 67 7-(4-Chlorobenzamidol-1-(4-ethyl-1-piperazinyl)-naphthalene A solution of 7-(4-chlorobenzamido)-1-(1-piperazinyi)-naphthalene (0.197 g, 5.39 mmol, the product of Example 12) in tetrahydrofuran (14 mL) was chilled to -78°C and butyllithium (0.454 mL, 1.13 mmol, 2.5 M) was added in three portions. The yellow solution was stirred 5 minutes, then ethyl iodide (0.045 mL, 0.566 mmol) was added and the reaction was allowed to warm to room temperature. The mixture was treated with saturated aqueous ammonium chloride and the solvent was removed at reduced pressure. The residue was taken up in methylene chloride and extracted with saturated aqueous sodium bicarbonate and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2.5 inches). Elution proceeded as follows: 7596 ethyl acetate / hexane (150 mL), nil; 9096 ethyl acetate / hexane (200 mL) and ethyl acetate (200 mL), 0.135 g of a light yellow foam. This foam was triturated with pentane and 0.112 g (5296) of the title compound was collected as a white powder. mp 173-174.5°C.
Analysis calculated for CI~H~,CIN,O: C, 70.13; H, 6.14; N, 10.67. Found: C, 70.21;
H, 6.32; N, 10.79.
Example 6f3 7-Amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (2.035 g, 5.07 mmol, preparation 4) in tetrahydrofuran (50 mL) was chilled to -78°C and butyllithium (2.03 mL, 5.07 mmol, 2.5 M) was added dropwise. The dark solution was stirred 10 minutes, then 1-t-butoxycarbonyl-3-pyrrolidinone (0.939 g, 5.07 mmol in 4 mL
tetrahydrofuran) was added dropwise with a 4 mL tetrahydrofuran rinse. The reaction was allowed to warm to room temperature and the solvent was removed. The residue was taken up in methylene chloride and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1.5 x inches). Elution proceeded as follows: 596 ethyl acetate / hexane (700 mL), unweighed forrun; 10°~6 ethyl acetate / hexane (200 mL), nil; 259'° ethyl acetate l hexane (300 mL), 0.94 g of 7-dibenzylamino-1-( 1-t-butoxycarbonyl-3-hydroxy-3-pyrrolidinyl)-naphthalene as a yellow oil which was suitable for use without further purfication. A
sample crystallized from ethyl acetate had mp 114-117°C. 'H NMR d 7.69 (d, J =
9 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.51 (d, J = 2 Hz, 1 H), 7.42-7.33 (m, 8 H), 7.32-7.22 (m, 3 H, SUBSTITIftf SHEET (RULE 26) partially obscutred by NMR solvent), 7.21-7.06 (m, 2 H), 4.81 (t, J = 21 Hz, 4 H), 3.99 (sym m, 1 H), 3.75 (sym m, 1 H), 3.5&3.35 (m, 1 H), 3.34.17 (m, 1 H), 2.29-2.10 (m, 1 H). 2.o2-l.ae (m, 1 H), 1.90 (s, 1 H), 1.49 (s, s H).
A solution of 7-dibeniylamino-1-(1-t-butoxycartionyl~-hydroxy-3-pyrrolidinyl).
naphthalene (1.0 g, 1.97 mmol) in benzene (20 mL) was chilled on wet ice (precipitate) and Burgess salt (0.89 g, 3.74 mol) was added all at once. The mixture was heated to 55°C for 2 hours. The reaction was cooled and extracted with water and brine. The combined aqueous phase was back extracted with ethyl ncetate and the combined organic layer was dried over calcium sullate. The organic layer was concentrated onto silica gel and flash chromatographed (1 x 2.5 inches). Elution with 696 ethyl acetate /
hexane ( 1300 mL) gave 0.764 g (7996) of a brown solid which wns a mixture of two dehydration products which were used directly in the next reaction.
A slurry of lithium aluminum hydride (1.78 g, 46.92 mmol) in tetrahydroturan (220 mL) was chilled to 0°C and the product of the above reaction (5.75 g, 11.73 mmol) was added in tetrahydrofuran (10 mL with 2 x 10 mL rinses). The mixture was refluxed 5 hours, chilled to 0°C and carefully quenched with sodium sulfate decahydrate. The reaction was filtered and the filter cake was rinsed well with methylene chloride. The filtrate wns concentrated at reduced pressure and the residue was taken up In methylene chloride. The organic phase was washed with brine, dried, and concentrated to give 4.58 g of a brown oil which was n 2:1 mixture of olefinic products as judged by integration of the methyl singlet at 2.48 ppm (major) and 2.31 ppm (minor) from the NMR spectrum. The mixture was used directly in the next step.
A mixture of the product of the above reaction (4.58 g) and 2096 palladium hydroxide on carbon (4.7 g) in ethanol (161 mL) and acetic acid (161 mL) was hydrogenated at about 50 psi for 5.5 hours. The reaction was filtered through Celite and the filtrate was concentrated at reduced pressure. The residue was neutralized with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (2 x 3.25 inches). Elution proceeded as follows: ethyl acetate (200 mL), nil; 196 triethylamine / 196 methanol / ethyl acetate (500 mL) and 296 triethylamine / 296 methanol / ethyl acetate (500 mL), nil; 596 triethylamine / 596 methanol / ethyl acetate (500 mL) and 1096 triethylamine / 1096 methanol / ethyl acetate (400 mL), 0.90 g of the title compound as a brown oil. 'H NMR 6 7.66 (d, J = 8.5 Hz, 1 H), 7.56 (d, *Trade-mark WO 94/21619 ' _.
J = 8 Hz, 1 H), 7.41 (d, J = 7 Hz, 1 H), 7.24 (s, 1 H, partially obscurred by NMR
solvent), 7.19 (t, J = 7.5 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 H), 4.20-3.96 (m, 1 H), 3.87 (br s, 2 H), 3.08 (t, J = 8.5 Hz, 1 H), 2.91-2.70 (m, 3 H), 2.45 (s, 3 H). This material was suitable for use without further purfication.
Example 69 7-Benzamido-1-( 1-methvi-3-pvrrolidinvl)-nachthalene A solution of 7-amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene (0.139 g, 0.615 mmol, product of Example 68) and triethylamine (0.103 mL, 0.738 mmol) in tetrahydrofuran (5 mL) was chilled to 0°C and benzoyl chloride (0.086 mL, 0.738 mmol) was added. The reaction was warmed to room temperature and stirred overnight.
The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic layer was washed with 0.5 N, sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows: 50% to 75% ethyl acetate / hexane (375 mL), nil; ethyl acetate (200 mL), nil; 296 triethylamine / 2% methanol / ethyl acetate (200 mL), 0.14 g of brown oil which partially crystallized. Recrystallization from ethyl acetate gave 0.058 g, (28%) of the title compound as white crystals. mp 137-145°C; 'H NMR d 8.57 (d, J = 2 Hz, 1 H), 8.06 (br s, 1 H), 7.95 (dd, J = 1.5, 8 Hz, 2 H), 7.86 (d, J = 9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.59-7.49 (m, 4 H), 7.40 (t, J = 7.5 Hz, 1 H), 4.15 (sym m, 1 H), 3.04 (t, J =
9 Hz, 1 H), 2.93-2.81 (m, 2 H), 2.80-2.68 (m, 1 H), 2.66-2.50 (m, 1 H), 2.47 (s, 3 H), 2.08-1.96 (m, 1 H). Analysis calculated for C~zHzzN~O: C, 79.97; H, 6.71; N, 8.48.
Found: C, 79.36; H, 6.72; N, 7.94.
Example 70 7-Amino-1-( 1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (5.0 g, 12.0 mmol, preparation 4) in tetrahydrofuran (300 mL) was chilled to -78°C and butyllithium (5.0 mL, 12.5 mmol, 2.5 M) was added dropwise to generate a dark red solution. A
tetrahydrofuran solution (40 mL) of 1-t-butoxycarbonyl-R-prolinal (2.61 g, 13 mmol) was added dropwise with a 10 mL tetrahydrofuran rinse. The reaction was stirred an additional 10 minutes, then carbon disulfide (0.95 mL, 16 mmol, predried over calcium sulfate) was added. The reaction color changed from green to brown and finally to orange. After stirring 30 minutes at -78°C, methyl iodide (0.82 mL, 13 mmol) was added and the reaction was allowed to warm to ambient temperature and stir 2 hours.
SUBSTITUTE SHEET (RULE 26) Aqueous ammonium chloride and ether were added and the phases were separated.
The organic layer was washed with water end brine, dried over magnesium suftate, concentrated onto silica gel and flash chromatographed (2 x 6 Inches). Elution proceeded ns follows: 296 ether / hexane (1 L), unweighed impurity; 596 ether / hexane (1000 mL), 1096 ether / hexane (1000 mL), end 2096 ether / hexane (1000 mL), 5.74 g (7896) of the xanthate intermediate as a mixture of diastereomers which was used directly in the next step.
A solution of the xanthate from the above reaction (5.74 g, 9.37 mmol) in toluene (300 mL) was heated to reflux and AIBN (0.26 g) (AIBN=azo(bis) isobutyronitrile) and tributyltin hydride (11.7 mL, 43.5 mmol) were added in three portions first at initial reflux and then after 1 and 2 hours of retlux. The reaction was refluxed an additional 1.5 hours, cooled to room temperature and allowed to stir overnight. The reaction was concentrated onto silica gel and flash chromatographed (2 x 8 inches). Elution proceeded as follows: hexane (1000 mL), unweighed tin t 5 impurities; 296 ether / hexane (2 L) and 396 ether / hexane (2 L), unweighed impurities;
596 ether / hexane (3 L), 3.07 g (6596) o/ 7-dibenzylamino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)- naphthalene as a hard yellow-green foam.
A mixture of 7-dibenzylamino-1-(1-t-butoxycarbonyt-pyrrolidin-2-(R)-ylmethyl) naphthalene (0.68 g, 1.34 mmol) and 2096 palladium hydroxide on carbon (0.25 g) In ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 50 psi for 8 hours.
Additional 2096 palladium hydroxide on carbon (0.25 g) was added and hydrogenation was continued overnight. The catalyst (0.3 g) was added a ti~ird time and hydrogenation was continued 24 hours more. The reaction was filtered through celite'~
and the pad was washed with ethanol. The filtrate was concentrated and the residue was taken up in ether. This organic phase was extracted with saturated aqueous sodium bicarbonate, water and brine, then it was dried and concentrated to give 0.368 g (8496) of the title compound as a tan Loam. A sample recrystallized from ether /
hexane as a light tan solid had mp 157-158.5°C. Analysis calculated for C?°H76N10?:
C, 73.59; t-i, 8.03; N, 8.58. Found: C, 73.47; H, 7.93; N, 8.37.
The S enantiomer of the title compound of Example 70 was prepared using the same procedure set forth in Example 70, except that 1-t-butoxycarbonyl-(S)-prolinal was used in place of 1-t-butoxycarbonyl-(R)-prolinal.
*Trade-mark Example 71 7-L4-Chlorobenzamidol-1-(pvrrolidin-2-(Rl-ylmethyll-naphthalene A solution of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphtha) ene (0.10 g, 0.306 mmol, product of Example 70) and triethylamine (0.085 mL, 6.1 mmol) in tetrahydroturan (5 mL) was chilled to 0°C and 4-chlorobenzoyl chloride (0.043 mL, 0.338 mmol) was added. The mixture was allowed to warm to room temperature and stir 2 hours. Ether was added and the reaction was extracted with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was concentrated onto silica gel and flash chromatographed (1 x 6 inches).. Elution proceeded as follows:
2096 ether / hexane, unweighed forrun; 3096 ether / hexane (200 mL) 0.096 g (68°~6) of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene as a white powder. A sample recrystallized from ether / hexane had mp 136.5-137 ° C; (a]p - -75.4°, c = 0.195 (chloroform). Analysis calculated for C~,H~CINzO,:
C, 69.74; H, 6.29; N, 6.02. Found: C, 69.75; H, 6.00; N, 6.00.
To a solution of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylme thyl)-naphthalene (0.09 g, 0.19 mmol) in ether (10 mL) was added ether saturated with gaseous hydrogen chloride (27 mL) in portions over several hours. The mixture was stirred overnight and concentrated. The residue was triturated with ether and 0.063 g (8096) of the title compound was collected as a faint pink solid salt. mp 230-231.5 ° C;
[a]p = -46.8°, c = 0.280 (methanol). Analysis calculated for Cz=Hz,CINzO - HCI ~ 0.5 HzO: C, 64.39; H, 5.90; N, 6.83. Found: C, 64.49; H, 5.38; N, 6.70.
The S enantiomer of the title compound of example 71 was prepared using the same procedure set forth in Example 71, except that 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(S)-ylmethyl)-naphthalene was used in place of 7-(4-chlorobenzamido)-1-( 1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene.
Example 72 7-Formamido-1-(pyrrolidin-2-(Rl-ylmethyll-naphthalene hydrochloride A mixture of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene (0.096 g, 0.294 mmol, product of example 70), triethylamine (0.055 mL, 0.395 mmol) and acetyl formyl anhydride (0.050 mL, 0.373 mmol) in tetrahydrofuran (5 mL) was refluxed 2 hours. Additional acetyl formyl anhydride (0.020 mL) was added and the reaction was stirred 1 hour more. The reaction was diluted with ether and extracted with water and brine. The organic phase was dried, concentrated, and flash SUBSTITUTE SHEET (RULE 26) ~ 1584~'~
~6-chromatographed on silica gel (1 x 4 inches). Elution proceeded as follows:
1096 ethyl acetate / hexane (100 mL), nil; 2096 ethyl acetate / hexane (350 mL), nil;
2596 ethyl acetate / hexane (750 mL), 0.076 g (7396) of 7-formamido-t-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene as a pale pink oil.
The oil from the above reaction (0.076 g, 0.214 mmol) was dissolved in ether and ether saturated with hydrogen chloride (10 mL) was added in 2 mL portions over 1 hour. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under a nitrogen stream and the residue was scurried in ether (20 mL).
The slurry was gently refluxed 1 hour and the materiel was triturated to yield the title compound as a light tan powder. mp 223.5-224°C; [aJo = -51.5°, c = 0.295 (methanol). Analysis calculated for C,eH,eN~O ~ HCI ~ 1.5 HzO: C, 60.47; H, 6.98; N, 8.81. Found: C, 60.65; H, 6.69; N, 8.72.
Examcle 73 7-Amino-1~1-piaerazinvll-nachthalene The product of Example 11 (7-benzamido-1-(1-piperazinyl)-naphthalene, (0.063 g, 0.19 mmol) was combined with hydrochloric acid in ethanol (4 mL) and refluxed 16 hours. The reaction was concentrated at reduced pressure and the residue was neutralized with 4 N sodium hydroxide and extracted with methylene chloride.
The organic phase was washed with brine, dried and concentrated to a tan solid (0.041 g).
The solid was recrystallized from ethyl acetate / hexane to give 0.020 g (4796) of the title compound as light tan crystals. mp 184-186°C. HRMS m/e calculated for C"H,~N,:
227.1419. Observed m/e 227.1405.
Example 74 7-(Imidazolo-f4.5-bl-pvridin-1-yll-1-(1-piperazinyl,)-naphthalene A two phase mixture of methylene chloride (50 mL) and water (100 mL) containing 7-amino-1-(1-piperazinyl)-naphthalene (5.05 g, 22.23 mmol) and sodium carbonate (2.36 g, 22.23 mmol) was treated with di-tert-butyl Bicarbonate (4.85 g, 22.23 mmol, in 40 mL methylene chloride) dropwise with a 10 mL methylene chloride rinse.
The reaction was stirred overnight, then the phases were separated. The organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1.5 x 3.5 inches). Elution proceeded as follows: 1096 ethyl acetate / hexane (700 mL), 1.6agof7-tert-butoxycarbonylamino-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as a yellow foam; 10°ro ethyl acetate / hexane (200 mL) and 3096 ethyl acetate / hexane SUBSTITUTE SHEET (RULE 26) -67.
(500 mL), 4.18 g of 7-amino-1-(4-tert-butoxycarbonyt-1-piperazinyl)-naphthalene as a brown foam which had ' H NMR d 7.67 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H), 7.35 (d, J = 2.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.01 (dd, J = 1, 7.5 Hz, 1 H), 6.95 (dd, J = 2.5, 8.5 Hz, 1 H), 3.90 (br s, 2 H), 3.05 (br s, 8 H), 1.51 (s, 9 H).
A mixture of 7-amino-1-(4-tent-butoxycarbonyl-1-piperazinyt)-naphthalene (0.523 g, 1.60 mmol, product of the above reaction), 2-chloro-3-nitropyridine-N-oxide (0.335 g, 1.92 mmol, product of preparation 5) and 4-dimethylaminopyridine (0.195 g, 1.60 mmol) in ethanol (40 mL) was refluxed 2 hours. The solvent was removed at reduced pressure and the residue was taken up in methytene chloride. The organic solution was washed with saturated aqueous sodium bicarbonate and brine and the aqueous washes were back extracted (5x) with methylene chloride. The combined organic phase was dried, concentrated onto silica get and flash chromatographed (1 x 3 inches). Elution proceeded as follows: 50% ethyl acetate / hexane (200 mL) and ethyl acetate / hexane (200 ml.), nil; 7096 ethyl acetate / hexane (100 mL) and ethyl acetate (300 mL), 0.458 g (61 %) of 7-(3-vitro-1-oxido~2-pyridylamino)-1-(4-tert-butoxycarbonyt-1-piperazinyl)-naphthalene as a dark red foam which was suitable for use without further purification. A sample recrystallized from ether / hexane as orange crystals had mp 191-193°C. Analysis calculated for C~,H~,NsOs: C, 61.92; H, 5.85; N, 15.04. Found: C, 61.59; H, 5.79; N, 14.54.
A mixture of 7-(3-vitro-1-oxido-2-pyridylamino)-1-(4-tert-butoxycarbonyl-t -pip erazinyl)-naphthalene (0.40 g, 0.86 mmol, product of the above reaction), ammonium formats (1.0 g, 17.2 mmol), and 10% palladium on carbon (0.15 g) in ethanol (30 mL) was refluxed 4 hour while continually returning sublimed ammonium formats back into the reaction. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was washed with water and brine, dried over calcium sulfate, and concentrated. The residue was flash chromatographed on silica gel (1 x 3 inches). Elution proceeded as follows: 2596 ethyl acetate /
hexane (100 mL), nil; 3596 ethyl acetate / hexane (250 mL), 0.25 g of product. The product was treated with activated carbon, filtered, and concentrated. The residue was recrystalfized trim ethyl acetate / ether to give 0.11 g (30%) of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl )-naphthalene as white crystals which were sensitive to air (turn brown on air exposure) and had mp 183-184°C. Analysis calculated for Cz4H~9N50z: C, 68.71; H, 6.97; N, 16.69. Found: C, 68.76; H, 6.58; N, 16.56.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ 1 a 8 45 7 PCT/US94/01206 ~8-A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tart-butoxycarbonyl-1-piperazinyl )-naphthalene (0.124 g, 0.296 mmol, product of the above reaction) and ethoxymethylenemalononitrile (0.47 g, 0.385 mmol) in isopropanol (7 mL) was refluxed 4 hour. Additional ethoxymethyienemalononitrile (0.035 g) was added and the reaction was refluxed overnight. The reaction was concentrated onto silica gel and flash chromatographed (1 x 3.5 inches). Elution proceeded as follows: 10% ethyl acetate / hexane (400 mL), nil; 20% ethyl acetate / hexane (300 mL), unweighed isopropoxymethylenemalononitrile; 20% ethyl acetate / hexane (50 mL) and 40%
ethyl acetate / hexane (300 mL), 0.082 g (65%) of 7-(imidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as a tan oily foam which was suitable for use as obtained which had'H NMR a 8.76 (d, J = 2 Hz, 1 H), 8.51-8.48 (m, 2 H), 8.20 (dd, J = 1.5, 8 Hz, 1 H), 8.04 (d, J = 9 Hz, 1 H), 7.84 (dd, J = 5, 8 Hz, 1 H), 7.65 (d, J =
8 Hz, 1 H), 7.49 (t, J = 8 Hz, 1 H), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.17 (d, J =
7.5 Hz, 1 H), 4.20-3.30 (br coalesced signal, 4 H), 3.16 (br s, 4 H), 1.51 (s, 9 H).
A solution of 7-rmidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl-1-pip erazinyl)-naphthalene (0.076 g, 0.177 mmol) in ethanol (6 mL) was treated with hydrogen chloride saturated dioxane (4 mL). The mixture was stirred 10 hours at room temperature and a fine precipitate formed. The solvent was removed at reduced pressure and the residue was dissolved in hot methanol and filtered. The filtrate was concentrated to about 4 mL at the boil and treated with ethanol (3 mL). The white crystals obtained on cooling were collected and washed with cold ethanol to give 0.022 g (3396) of the dihydrochloride of the title compound. mp > 250° C.
Analysis calculated for C=°H,~NS ~ 2 HCI: C, 59.71; H, 5.26; N, 17.41. Found: C, 59.72; H, 5.29; N, 16.62.
Example 75 7-(1 2 3-Triazolo-14,5-bl-yyridin-1-y~-1-(1-piperazinyl)-naphthalene A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tart-butoxycarbonyl-1-piperazinyl )-naphthalene (0.038 g, 0.0906 mmol, intermediate of example 74) in 5% sulfuric acid (1.5 mL, precooled to 0°C) was treated with sodium nitrite (0.0066 g, 0.095 mmol) in water (0.1 mL) with a water rinse (2 x 0.1 mL). The heterogeneous mixture was stirred 40 minutes at 0°C. The reaction was diluted with ice and neutralized with 1 N sodium hydroxide. The reaction was extracted with methylene chloride and this organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated to yield 7-(1,2,3-triazolo-[4,5-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl- 1-SUBSTITUTE SHEET (RULE 26) piperazinyl)-naphthalene as a brown oil (0.034 g, 87%) which was suitable for use without purification. A sample treated with activated carbon in methylene chloride and then recrystallized from ether / hexane had mp 173-175°C. Analysis calculated for C~,H~eNaOz; C, 66.96; H, 6.09; N, 19.52. Found: C, 66.61; H, 6.18; N, 19.28.
A solution of 7-(1,2,3-triazolo-[4,6-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl-piperazinyl)-naphthalene (0.075 g, 0.174 mmol, product of the above reaction) in ethanol (4~mL) was treated with hydrogen chloride saturated dioxane (4 mL) and the mixture was stirred at room temperature 10 hours. The solvent was removed at reduced pressure and the residue was dissolved in hot methanol. The methanol solution was filtered hot and the filtrate was concentrated at the boil to about 1 mL.
Yellow crystals formed on cooling. These crystals were collected to give 0.031 g (48%) of the hydrochloride the title compound. mp >250°C. Analysis calculated for C,~H,eNa HCI: C, 62.21; H, 5.22; N, 22.91. Found: C, 62.11; H, 5.11; N, 22.53.
Example 76 1-(4-Methylpiperazin-1-yll-7-(pyrimid-5-yl)naphthalene A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.250 g, 0.67 mmol), bis(triphenylphosphine)palladium[II] chloride (0.025 g, 0.036 mmol), 5-trimethylstannylpyrimidine (0.178 g, 0.74 mmol, from Preparation 6), triethylamine -(0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethylformamide (12.5 mL) was heated between 100°C to 115°C under nitrogen for 45 minutes. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica get (approximately 25 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide] to afford the title compound (0.060 g, 0.20 mmol, 29%) as a pale yellow foam: R, = 0.15 in 2096 methanol in ethyl acetate;
"C NMR (CDCI3) d 157.3, 155.0, 149.8, 134.6, 134.5, 130.8, 129.9, 129.0, 127.1, 124.0, 123.4, 122.1, 116.0, 55.4, 52.7, 45.9; LRMS (m/z, relative intensity) 304 (M+, 7), 240 (100), 225 (15), 196 (16), 169 (44), 155 (33), 141 (16); HRMS m/e calculated for C,9H~oN, 304.1690. Observed m/e 304.1689.
Example 77 7 (5-CYanopyrid-3-yl~~-1-l4-methylpigerazin-1-yl)naphthalene A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.527 g, 1.53 mmol), bis(triphenylphosphine)palladium[II] chloride (0.537 g, 0.77 WO 94/21619 ~ 15 8 4 5'~ PCT/US94101206 -7o-mmol), 5-cyano-3-trimethylstannylpyridine (0Ø450 g, 1.69 mmol, from preparation 7), triethylamine (1.02 mL, 7.34 mmol), lithium chloride (0.194 g, 4.59 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethytformamide (6 mL) was heated between 100°C to 115°C under nitrogen for 1.5 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 596 methanol in ethyl acetate to afford the title compound (0.170 g, 0.52 mmol, 34%) as a pale yellow foam: R, = 0.40 in 596 methanol in ethyl acetate; ' H (CD,OD) a 9.08 (d, J_=2.2 Hz, 1 H), 8.82 (d; J=2.2 Hz, 1 H), 8.43 (t, J_=2.0 Hz, 1 H), 8.36 (br s, 1 H), 7.92 (d, J=8.5 Hz, 1 H), 7.70 (dd, _ -J=1.8 and 8.5 Hz, 1 H), 7.57 (br d, J=8.2 Hz, 1 H), 7.44 (t, J=7.8 Hz, 1 H), 7.17 (d, J=7.3 Hz, 1 H), 3.20-3.00 (br s, 4H), 2.85-2.65 (br s, 4H), 2.40 (s, 3H);
LRMS (m/z, relative intensity) 328 (M', 100); HRMS m/e calculated for C=,HzoN, 328.1690.
Observed m/e 328.1715 Example 78 General procedure for the synthesis of (1-piperazinvllnaphthyl-7-vl ethers.
To a flame dried round bottom flask was added 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene (0.30 g, 1.23 mmol), anhydrous N,N-dimethylformamide (3 mL), and 6096 dispersion of sodium hydride in mineral oil (0.060 g; 1.47 mmol, 1.2 eq). The resulting suspension was heated for twenty minutes at 40° C, and the resulting reaction mixture was then allowed to cool to room temperature. A suspension of the appropriate alkylating agent or appropriate electrophile (1.35 mmol, 1.1 eq), anhydrous DMF (1 mL) and 6096 sodium hydride (0.075 grams 0.00183 moles) was then added slowly over minutes in three portions to the reaction mixture, and the resuwng mixture was heated at 80°C. The progress of the reaction was monitored by TLC, and reaction completion was determined by consumption of 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene as determined by TLC. Upon determination of reaction completion, DMF was then removed in vacuo, and the residue was partitioned between methylene chloride (40 mL) and saturated sodium bicarbonate solution (40 mL). The organic layer was removed, dried (Na~SO,), and concentrated in vacuo. The resulting residue was purified by flash column chromatography using silica gel (15 grams) and elution with 12:1:0.04 (CHzCh:
methanol: NH,OH) to afford the title compound.
SUBSTITUTE SHEET (RULE 26~
_71 Usfng the above general procedure, the following compounds were prepared:
A. 2 (8 (Methylpiperazin-1-yl)napthalen-2-yioxylnicotinonitrile 2-Chloro-3-cyanopyridine was the electrophile. Chromatography afforded the title compound (3396) as an amorphous solid: HRMS m/e calculated for C~,H~°N~O
5 344.1637. Observed m/e 34.4.1618; "C NMR (CDCI,) d 46.2, 52.9, 55.6, 97.7, 114.6, 115.0, 115.7, 118.1, 121.1, 123.4, 125.8,129.9, 130.1, 132.7, 143.5, 149.6, 150.0, 151.5, 163.9.
Example 79 8 (4 Methylpiperazin 1 yl)naphthalene-2-carboxylic acid phenylamide To a flame dried 3-neck flask were added 7-trifluoromethylsulfonyloxy-t-(4-methylpiperazin-1-yl)naphthalen a (0.958, 2.54 mmol), aniline (0.35 mL, 3.81 mmol), and triethylamine (0.39 mi_, 2.79 mmol). A balloon of carbon monoxide provided a CO
atmosphere above the reaction mixture via the reflux condenser. The reaction contents were heated at 100 ° C for ten minutes. The solution was then cooled to 70 ° C, and bis(triphenylphosphine)palladium(II) chloride (0.036 g, .05 mmol, 2 mo196) was added to the reaction solution. The resulting reaction mixture was stirred at 100°C for 19 hours. Then the CO balloon was refilled with C0, additional triethylamine (approx. 0.5 mL) was added, and this mixture was stirred at 100°C for 5 hours. Ethyl acetate (25 mL) was added to the cooled reaction mixture, and this mixture was then filtered through Celitem. The filtrate was concentrated in vacuo. The residue was purified using flash column chromatography using silica gel (30 g) and elution with 596 methanol in ethyl acetate to afford the title compound (0.090 g, 1096) as an amorphous solid: R, _ 0.42 in 9:1:0.1 methylene chloride/methanol/ammonium hydroxide; HRMS m/e calculated for CzzHz,N,O 345.1843. Observed m/e 345.1873; "C NMR (CDCI,) a 46.0, 52.9, 55.4, 115.9, 120.3, 123.2, 123.3, 123.7, 124.6, 128.0, 128.1; 129.1, 131.5, 136.2, 138.1, 150.5, 167Ø
Example 80 8 (4 Methylpiperazin 1 yl)naphthalene-2-carboxylic acid 4-chlorobenzvlamide A mixture of 7-trifluoromethylsuHonyioxy-1-(4-methylpiperazin-1-yl)naphthalene (9.0 g, 24 mmol), bis (triphenylphosphine) palladium chloride (0.36 g, 0.51 mmol) and methanol (90 mL) was warmed to 60°C under a balloon of carbon monoxide for 96 hours. The reaction was cooled to room temperature and charged with additional catalyst (0.28g, 0.396 mmol). The mixture was again placed under a carbon monoxide SUBSTITUTE SHEET (RULE 2b~
WO 94/21619 21 ~ g 4 ~ ~ PCTIUS94101206 atmosphere and refluxed 40 hours. The reaction was cooled filtered and concentrated to a brown oil. This residue was flash chromatographed on silica gel (300 g).
Elution was 30: 1: 0.03 ethyl acetate, methanol, ammonium hydroxide to afford 2.7 g (39.5%) of methyl 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylate as a light yellow solid: tlc:
R, = 0.32 (10: 0.5: 0.05, ethyl acetate, methanol, ammonium hydroxide), "C NMR
a 167.36, 150.32,136.85. 128.64,128.39, 127.83, 126.58, 125.89,125.19,123.37, 115.57, 55.22, 52.33, 52.17, 45.54, HRMS m/e calculated for C"Hz°N=O~: 284.152.
Observed m/e: 284.1513.
A mixture of the above ester (1.56 g, 5.48 mmol), methanol (50 mL) and lithium hydroxide (1.15 g, 27.4 mmol) was refluxed 22 hours. The reaction was concentrated and the residual solid was treated with hydrochloric acid in dioxane (32.9 mL, 32.9 mmol, 1 N). Water (3 mL) was added to yield a clear solution which was concentrated in vacuo to afford 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylic acid hydrochloride as a solid which also contained lithium hydrochloride. This material was used without purification and assumed to be a quantitative yield reaction. HRMS m/e calculated for C,eH"N=O=: 270.1370. Observed m/e: 270.1360.
A mixture of the above acid (0.25 g, 0.82 mmol), methylene chloride (4 mL), N-methylmorpholine (0.31 mL, 2.87 mmol), 1-hydroxy benzotriazole hydrate (0.12 g, 0.9 mmol), 4-chlorobenzylamine (0.1 mL, 0.82 mmol) and 1-cyclohexyl-3-(7-morpholinoethyl) carbodiimide p-toluenesulfonate (0.69 g, 1.62 mmol) was stirred 17 hours at ambient temperature. The reaction was diluted with water (10 mL) and methylene chloride (10 mL) and adjusted to pH 9 by addition of saturated aqueous sodium carbonate. The phases were separated and the organic layer was dried over sodium sulfate and concentrated to a yellow solid. This material was purfied by flash chromatography on silicon gel (6 g). Elution with 12: 1: 0.04, metnyiene crnonae, methanol, ammonium hydroxide gave 0.07 g (21.8%) of the title compound as a solid:
mp 72-74°C; tlc: R, = 0.28 (12: 1: 0.04, methylene chloride, methanol, ammonium hydroxide); "C NMR d 168.04, 150.69, 137.09, 136.16, 133.17, 130.82, 129.01, 128.90, 128.77, 128.18, 127.91, 123.84, 123.30, 123.07, 115.61, 55.47, 53.10, 46.13, 43.34.
HRMS m/e calculated for Cz,Hz,CIN,O: 393.1607. Observed m/e: 393.1642.
SUBSTIME SHEET (RULE 26) ~8 45'x -73-ExamDIe 81 7 (3-Methoxyphenvl)-1-(4-methylDioerazin-1-yl)naphthalene A mixture of 3-methoxy-1-bromobenzene (0.089 mL, 0.71 mmol), 7 trimethylstannyl-1-(4-methylpiperazin-1-yl)naphthalene (0.25 g, 0.64 mmol), bis (acetonitrile) palladium chloride (0.0085 g, 0.032 mmol), tri(3-methoxyphenyi)phosphine (0.023 g, 0.064 mmol), and butylated hydroxytoluene (BHT, about 0.001 g, antioxidant) in dimethyl formamide (12 mL) was warned to 110°C for 2 hours. The reaction was cooled to room temperature and diluted with 1 N aqueous lithium chloride (25 mL) and 1 N sodium hydroxide (2 mL); then extracted with ether (3X). The combined ether layer was washed with 1 N aqueous lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was purfied by flash chromatography on silica gel (1x2.5 inches). Elution proceeded as follows:
7596 ethyl acetate / hexane, 200 mL, nil; 296 methanol / ethyl acetate 200 mL and 1096 methanol / ethyl acetate, 200 mL, 0.084 g of an oil. This oil was further purled by kugelrohr distillation (1 mm Hg). The distillation proceeded as follows: 110-130°C, 0.014 g of a mixture of the title product and 7-methyl-1-(4-methylpiperazin-1-yl)naphthalene: 200-220°C, 0.062 g (2396) of the title compound as a yellow oil: 'H NMR d 8.43 (incompletely resolved dd, J = 1.2Hz, 1 h), 7.90 (d, J = 9 Hz, 1 H), 7.74 (dd, J = 2, 8.5 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H), 7.43 (sym m, 2 H), 7.34 (dt, J = 1.5, 7.5 Hz, 1 H), 7.29 (5, J = 2 Hz, 1 H), 7.14 (dd, J = 1, 7.5 Hz, 1 H), 6.96 (ddd, J = 1, 2.5, 8 Hz, 1 H), 3.92 (s, 3 H) 3.20 (br s, 4 H), 2.75 (br s, 4 H), 2.44 (s, 3 H). The product was dissolved in chloroform and HCL gas was bubbled through the solution to form the hydrochloride salt. Concentration of this solution to about 1 mL. at the boil and addition of about 1 mL of ether caused the white crystalline product to precipitate. The hydrochloride salt weighted 0.057 g: mp 236-238°C. Analysis calculated for C~ZH~,NzO ~
HCI: C, 71.63;
H, 6.83; N, 7.59. Found: C, 71.31; H, 6.92; N, 7.59.
Example 82 1 (1 Methylpiperidin-4-yl)-7-naphthalene carboxylic acid 4-chlorobenzylamide A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethylsuifonytoxynaphthalene (1.0 g, 2.69 mmol), 4-chlorobenzylamine (0.59 mL, 4.84 mmol) and bis (triphenylphosphine)palladium chloride (0.095 g, 0.13 mmol), and triethylamine (0.56 mL, 4.04 mmol) was blanketed with an atmosphere of carbon monoxide (with the aid of a balloon) and heated to 110-120°C for 2 hours. Additional 4-chlorobenzylamine SUBSTITUTE SHEET (RULE 26) (0.2 mL) was added and the reaction was heated under carbon monoxide for 17 hours more. The reaction was cooled to room temperature and taken up in ethyl acetate.
The mixture was extracted with water and brine, dried over caldum sulfate, and concentrated. The residue was flash chromatographed on silica gel (1.5 x 2.5 inches).
Elution proceeded as follows: ethyl acetate, 350 mL, nil; 296 methanol / ethyl acetate, 300 mL, nil; 496 methanol / 196 triethylamine / ethyl acetate, 200 mL, 0.085 g of impure product. Continued elution with 496 methanol / 196 triethylamine / ethyl acetate, 200 mL, 0.266 g (2596) of the title compound as a yellow oil. 'H NMR (DMSOda) 6 8.74 (s, 1 H), 7.90 (d, J=8.5 Hz, 1 H), 7.73 (dt, J=1.5, 8.5 Hz, 2H), 7.58-7.48 (m, 2H), 7.35 (s, 4H), 6.63 (br t, J=6 Hz, 1 H), 4.70 (d, J=6 Hz, 2H), 3.42 (quintuplet, J=8 Hz, 1 H), 3.05 (br d, J=12 Hz, 2H), 2.38 (s, 3H), 2.23 (sym m, 2H), 1.99-1.92 (m, 4H). HRMS
m/e calculated for C~,H~C1 NzO: 393.1733. Observed m/e: 393.1747.
Synthesis of intermediates used in the above Examples are described in the preparations below.
Preparation 1 7-hydroxy-1-(4-methyl-1-piperazinyly-3.4-dihydronaphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol, Corey and Estreicher, Tetrahedron Lett., 1981, 22, 603) and 1-methylpiperazine (2.2 mL, 19.83 mmol) were dissolved in dry THF (90 mL) and chilled to 0°C. Titanium tetrachloride (0.91 mL, 8.3 mmol) was allowed to run down the side of the reaction vessel into the reaction via syringe to give a vigorous reaction which caused the solution to tum orange-red. The mixture was allowed to warm to ambient temperature and stir 1.5 hours. A 2:1 mixture of water and concentrated ammonium hydroxide (90 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried over calcium sulfate and concentrated to give 1.48 g of crude enamine which was used immediately without characterization.
(This enamine was not stable to chromatography but did show a characteristic signs!
in the 'H NMR for the enamine vinyl proton at 5.28 ppm with a 4.7 Hz coupling constant).
Preparation 2 7-Hydroxy-1-(4-meth5rl-1-piperazinyl~~-naphthalene 1096 Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene (1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture was cooled, filtered, and concentrated. The product was purified SUBSTITUTE SHEET (RULE 26) by flash chromatography on silica gel (1 x 6 inches). Elution with 50 96 ethyl acetate/hexane followed by 10096 ethyl acetate gave 0.51 g (3496) of the title product as a light pink foam. A sample was recrystallized from ether to give a seam colored solid for analysis: mp 184-185°C. Analysis calculated for C,6H,eN=O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05; H, 7.03; N, 11.42.
Preparation 3 7 Trimethylstannvl-1-(4-methyl-1-piperazinyll-naahthalene 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (2.0 g, 5.34 mmol), hexamethylditin (1.92 g, 5.86 mmol), lithium chloride (0.68 g, 16 mmol), tetra (triphenylphosphine) palladium (0.24 g, 0.21 mmol) and butylated hydroxytoluene (a few crystals, antioxidant) were combined in dry dioxane (50 mL) and refluxed 45 minutes.
The mixture was cooled and quenched with saturated ammonium chloride (50 mL).
The mixture was extracted with ether (2x) and the combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated to a brown oil.
Flash chromatography on silica gel (2 x 4 inches) with 5096 ethyl acetate/hexane elution gave 0.77 g (3796) of the title product as a light brown oil which slowly solidified. The product was suitable for use in subsequent reactions but was not analytically pure:'H
NMR d 8.36 (s with Sn coupling, 1 H), 7.80 (d, J_ = 8 Hz, 1 H), 7.61-7.51 (m, 2H), 7.40 (t, J = 8 Hz, 1 H), 7.09 (dd, J = 1, 7.5 Hz, 1 H), 3.2 (br s, 4H), 2.75 (br s, 4H), 2.46 (s, 3H), 0.39 (s with Sn coupling of 55.0 and 52.5 Hz, 9H).
Preparation 4 8-Bromo-2-(dibenzylamino)-naphthalene A mixture of dibenzylamine (70.8 mL, 0.368 mol), 8-bromo-2-tetralone (82.86 g, 0.368 mol, U. S. patent 4,897,405 A), dry toluene (1000 mL), and p-toluenesulfonic acid (0.83 g, 4.36 mmol) was refluxed 2 days with azeotropic removal of water. Most of the toluene was distilled away from the reaction and the residual material was dried in vacuo about 12 hours. The crude enamine was obtained as an orange oil and was used directly in the next step. 'H NMR d 7.41-7.17 (m, 13 H), 6.97 (d, J = 7.3 Hz, 1 H), 6.72 (t, J = 7.6 Hz, 1 H), 5.83 (s, 1 H), 4.54 (s, 4 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.55 (dd, J = 8.5, 6.6 Hz, 2 H).
The enamine from the above reaction was dissolved in tetrahydrofuran (2000 mL) and chilled to 0°C. Chloranil (90.48 g, 0.368 mol) was added in portions over 10 minutes. The black solution was stirred 1.45 hours at 0°C, then the solvent was SUBSTITUTE SHEET (RULE 26) ~'~58457 removed at reduced pressure. Tha residua was taken up in methylene chloride (760 mL) and filtered through Cattle to remove an insoluble yellow material (discarded).
Saturated sodium carbonate (600 mL) was added to the filtrate and the two phase mixture was vigorously stirred 15 minutes. The mixture was again filtered tfttoughC~lite*
to remove a greenish solid (discarded). Tt~e phases were separated from the filtrate and the organic layer was washed with saturated sodium carbonate and then brine.
The solution was dried over calcium sulfate end concentrated onto silica gel and applied to a flash chromatography column (4 x 4 Inches silica gel). Elution proceeded as follows: hexane (500 mL, n11); 596 ether / hexane (2 L, nil); b% ether /
hexane (12 L, unweighed orange oil product). The oil was triturated with 5096 ett~er:hexane (500 mL) to yield the tan product, 8-bromo-2-(dibenzylamino)-naphthalene (72.15 g).
The residues from the trituration were rechromatographed as above to afford an additional 18.95 g of product. The combined yield was 91.1 g, 61%. mp 102.5-103°C;'H NMR
d 7.64-7.60 (m, 3 H), 7.37-7.24 (m, 11 H), 7.13 (dd, J = 9, 2.6 Hz, 1 H), 7.00 (t, J = 7.8 Hz, 1 H), 4.80 (s, 4 H). Analysis calculated for C"H,°8rN: C, 71.65; H, 5.01; N, 3.48.
Found: C, 71.24; H, 4.65; N, 3.49.
Preparation 6 2-Chloro-3-nitropyridine-N-oxide 2-Chloro-3-nitropyridine (0.69 g, 4.35 mmol) was chilled to 0°C and trifluoroacetic acid (9 mL) was slowly added followed by 3096 hydrogen peroxide (1 mL). The solution was warmed to 70°C for 1.5 hours, cooled to 0°C and excess peroxide was decomposed by dropwise addition of dimelhylsutfide (1 mL) and stirring 0.5 hours. The reaction was concentrated at reduced pressure onto silica gel and (lash chrornatographed (1 x 3 inches). Elution proceeded as follows: 5096 ethyl acetate /
hexane (175 mL), nil; 7596 ethyl acetate / hexane (175 mL), 0.589 g (7796) of 2-chloro-3-nitropyridine-N-oxide as an orange solid suitable for use without further purification. A
sample recrystallized from ethyl acetate / hexane had mp 98-100°C.
Analysis calculated for CSH~CINzO~: C, 34.41; H, 1.73; N, 16.05. Found: C, 34.75; ti, 1.67; N, 15.80.
*Trade-mark 2~y5~ ~~~
-n.
Preparation 6 5-Trimethylstenn~rlp~rrimidine A mixture of 5-bromopyrimidine (4.00 g, 25.16 mmol), hexamethylditin (9.06 g, 27.67 mmol), lithium chloride (1.27 g, 30.19 mmol), tetrakis(triphenylphosphine) palladium (1.13 g, 0.981 mmol), 2,6-di-tert-butyl-methylphenol (approximately 0.01 g), and dioxane (45 mL) was heated at reflux under nitrogen for 7 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 200 g) and elution with ethyl acetate/hexanes [1:1 J to afford the title compound (4.75 g, 19.6 mmol, 78%) as a clear, colorless liquid: R, = 0.6 in ethyl acetate/hexanes [1:1 J;'H NMR (CDCI,) a 9.11 (s, 1 H), 8.70 (s, 2H), 0.38 (s, 9H); "C NMR (CDCh) d 162.8, 158.5, 134.4, -9.6.
Preparation 7 5-Cyano-3-trimethylstannylpyridine A mixture of 3-bromo-5-cyanopyridine (5.84 g, 31.91 mmol), hexamethylditin (11.49 g, 35.10 mmol), lithium chloride (1.62 g, 38.29 mmol), tetrakis(triphenylphosphine)palladium (1.44 g, 1.24 mmol), 2,6-di-tert-butyl-4 methylphenol (approximately 0.01 g), and dioxane (60 mL)was heated at reflux under nitrogen for 8 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 200 g) and elution with ether/hexanes [1:1 J to afford the title compound (1.98 g, 7.41 mmol, 23%) as a pale yellow solid: mp, 77.0-79.0°C; R, =
0.65 in ether/hexanes [1:1J; 'H NMR (CDCI,) a 8.80 (dd, J=1.5 and 2.4 Hz, 2H), 8.03 (dd, J=1.5 and 2.1 Hz, 1 H), 0.39 (s, 9H).
The compounds of formula I of the present invention described in the above Examples were assayed for 5-HT", and 5-HT,° affinity using the aforementioned procedures with ICSOs of less than 0.60 NM for at least one of the above affinities.
SUBSTITUTE SHEET (RULE 26~
~a the R enantiomers at the chiral carbon designated by an asterisk in formula I
are preferred.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to hereih (e.g. alkoxy), may be linear or branched, and they may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
The following compounds are preferred:
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzamido-1-(1-piperazinyl)-naphthalene;
7-Acetamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxycarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Nitro-2-pyridinylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Hydroxy-3-methyl-1-butynyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(2-Ethylsulfonyl)ethenyl-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Methylaminosulfonylphenyl)-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methylsulfonylaminophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene;
7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(3-Fluorophenyl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Benzyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzoyloxy)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(Imidazolo[4,5-b)pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ ~ PCT/US94/01206 7-(Benzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Cyanobenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(1,2,3-Triazolo[4,5-b)pyridin-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(5-Trifluoromethylbenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
7-(6,7-Dichlorobenzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxymethyl]quinoline;
1-Methyl-4-~7-[2-(4-chlorophenyl)thiazol~-ylmethoxy)naphthalen-1-yl}piperazine;
1-Methyl-4-[7-(5-chloro-thiophen-2-ylmethoxy)napthalen-1-yl)piperazine;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid phenylamide;
7-Amino-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(Imidazolo [4,5-b]pyridin-1-yl)-1-(1-methyl-4-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido-1-( 1-methyl-4-piperidinyl)-naphthalene;
7-Amino-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(3-Nitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-(Imidazolo[4,5-b)pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene;
7-Benzamido-1-( 1-methyl-3-piperidinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-propyl-1-piperazinyl)-naphthalene;
7-(4-Chlorobenzamido)-1-(4-ethyl-1-piperazinyl)-naphthalene;
7-Amino-1-( 1-methyl-3-pyrrolidinyl)-naphthalene;
7-Benzamido-1-(1-methyl-3-pyrrolidinyl)-naphthalene;
7-Formamido-1-(pyrrolidin-2-(R)-ylmethyl)-naphthalene hydrochloride;
7-Amino-1-( 1-piperazinyl)-naphthalene;
7-(Imidazolo-[4,5-b)-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene; and 7-(1,2,3-Triazolo-[4,5-b)-pyridin-1-yl)-1-(1-piperazinyl)-naphthalene;
The following compounds are particularly preferred:
7-(Imidazolo [4,5-b) pyridin-1-yl)-1-(I-methylpyrrolidin-3-yl)naphthalene;
7-(4-Chlorobenzamido)-1-(pyrrolidin-2-(R)-ylmethyl)naphthalene;
2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxy)nicotinonitrile;
1-(4-Methylpiperazin-1-yl)-7-pyrimidin-5-yl)naphthalene;
7-(5-Cyanopyridin-3-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
1-(Piperazin-1-yl)-7-(pyrimidin-5-yl)naphthalene;
SUBSTITUTE SHEET (RULE 26) ~ ~ ~~r~
'~ -s-7-(4-Chlorobenzamido-1-(4-methylpiperazin-1-yl)naphthalene;
7-(3-Methoxyphenyl) 1-(4-methyipiperazin-1-yl)naphthalene;
7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene;
8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide;
7-Pyrimidin-2-yloxy-1-(4-methylpiperazin-t-yl)naphthalene;
7-(4-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)-naphthalene;
7-(Benzimidazol-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene; and &(1-Methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide.
Other compounds believed to be most preferred are the following:
~p 1-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-4-methyl-piperazine;
4-{7-[3-(4-Chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-naphthalen-1-yl}-1-methyl-piperidine;
7-(3-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene; and 7-(4-Methoxyphenyl)-1-(1-methylpiperidin-4-yl)-naphthalene.
The present invention also relates to a pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, Alzheimers disease, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carver.
The present invention also relates to a method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, Alzheimers disease, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ 1 ~ ~ ~ ~ 7 PCT/US94/01206 _7_ (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a method for treating disorders arising firom deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a compound of the fom~ula R Ri \ \
I
/ /
where R, is of the formulae -N N-R3, N-R3, or R3 ~R3 N N
or ~a IV V
Rz is (Methyl),Sn- or (Butyl)3Sn-; R, is hydrogen , C, to Ce alkyl, C, to Cs alkylaryl, or aryl; a is 0, 1, or 2; and a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are SUBS?ITUTE SHEET (RULE 26) y~
-7~1-independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C, to C~
alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C, to C~ alkoxy.
These compounds include all optical isomers of formula I (e.g. R and S
enantiomers) and their racemic and diastereomeric mixtures. When R, is SUBSTITUTE SHEET (RULE 26) n WO 94/21619 . "' PCT/US94/01206 ~1~8~~~
H N
~a the R enantiomers at the chiral carbon designated by an asterisk in formula I
are preferred. These compounds are useful as intermediates in preparing compounds of formula I.
Detailed Description of the Invention Compounds of formula I of this invention where R' is of the formula II are prepared by the following reaction of an o-tetralone of formula V with a suitable piperazine of formula VI.
SUBSTITUTE SHEET (RULE 26) 15 ~ ~5'~ _$ , _ w ! + H-N N-R3 i VI
,o I I
, 5 N~ N
I
NJ N
R
w w w w ~/ I I
The so called enamines of formula VII are generally prepared by this reaction in the presence of an acid catalyst such as, for example, p-toluenesuffonic acid or titanium tetrachloride. If desired, the water formed as a by-product of the reaction may be effectively removed from the reaction as it is formed by the use of a reagent such as SUBSTITUTE SHEET (RULE 26) WO 94/21619 e7 ~ PCT/US94/01206 molecular sieves or calcium sulfate, or by azeotropic removal employing a Dean Stark trap with a refluxing solvent. The reaction is typically run in n reaction inert solvent such as benzene, toluene, tetrahydrofuran, or methylene chloride, at a temperature of from about -78°C to about 150°C. When titanium tetrachloride is used as the acid catalyst, the preferred temperature for the reaction is from about -78°C to about 25°C.
When azeotropic water separation is employed, the preferred reaction temperature is the boiling temperature of the particular reaction solvent.
In general, the a tetralones of formula V, for example, where Rz is -OH, -NOz, or -NHZ are known in the literature and can be readily prepared by those skilled in the art, such as, for example 7-amino-a-tetralone, (J. Med. Chem., 1976, 19, 472) and 7 hydroxy-a-tetralone, (Tetrahedron Lett., 1981, 22, 603). Other a tetralones of formula V are readily prepared using the alkylation, acylation, and organometallic reactions described herein and in standard synthesis texts, for example Organic Synthesis, wiev, New York). The piperazines of formula VI are commercially available or can be made using methods known in the art.
The enamines of formula VII may be converted to compounds of formula I by an oxidative process. The reaction may be carried out using a variety of methods known in the art. Among the acceptable oxidizing agents are noble metal catalysts, such as, palladium or platinum on activated carbon if desired, chloranil, and sulfur. The reactions can be carried out in a reaction inert solvent for example, toluene, xylene, tetrahydrofuran, methylene chloride, preferably toluene or xylene, however a solvent is not always necessary, especially for oxidations carried out with elemental sulfur. The oxidation reactions generally proceed at a temperature of about 0°C to about 250°C.
Preferred temperatures for the oxidation depend on the particular oxidant in use and are about 60°C to about 150°C for noble metal catalytic oxidation, about 150°C to about 250°C for sulfur oxidation and about 0°C to about 100°C for chloranil oxidations. From 1 to 5 equivalents, preferably 2-4 equivalents, of an additive such as dicyclopentadiene or [2,2,2) bicyclooctene may be added to the reaction to reduce the amounts of enamine reduction side products which may fomn competitively with the desired naphthalene product.
Additional compounds of formula I may also be formed using standard chemical transformations on other compounds of formula I. For example, when Rz is R,(C=O)NH- or R,(C=O)O-, these groups may be hydrolyzed in the presence of SUBSTINTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 aqueous acid or base to form -NHz and -OH groups, respectively. These standard hydrolysis reactions may be carried out in water with any of a variety of acids or bases (for example HCI, HBr, NaOH, or KOH, preferably acid for amidehydrolysis and base for ester hydrolysis) and a cosohrent (methanol or tetrahydrofuran, for example) may be used if desired to promote dissolution of I in the medium. The reaction may be carried out at a temperature of from about 0°C to about 150°C.
The preferred reaction temperature is about 20°C to about 40°C for basic hydrolysis and about the boiling temperature of the mixture for acidic hydrolysis.
Ri Ri t0 R2 w w R2 w w / / / /
R~=Ra ( C=0 > 0- , Rz=OH , NH2 R4 ( C=0 > NH-Additional compounds of formula I may be prepared by a reaction using an alkylating or acylating agent (alkyl halide, mesylate, triflate, etc., or arylalkyl halide, mesylate, triflate, etc., or an alkyl or aryl anhydride, or an alkyl or aryl carboxylic acid chloride, etc.) with compounds of formula I where Rz = -NHz or -OH. Suitable alkylating agents could include compounds of the formulae R,-(CHz)ti Y or RS-(CHz)d Y
where b is 0 to 3 and Y is a suitable leaving group, such as, for example, Br, I, or triflate. Suitable acylating agents could include acid chlorides (e.g. R;
(CH2)e (C=O)-CI
or R5-(CHz)e (C=O)-CI) or acid anhydrides (e.g. (R4 (CHz)e (C=O))z O or (R5-(CHz)d (C=O))z-O, where b is 0 to 3). The reaction may be carried out in a reaction inert solvent such as tetrahydrofuran and dichloroethane for the alkylating and acylating reactions. Preferred solvents depend on the solubility of the reagents and the selection thereof would be known to one skilled in the art. These alkylation or acylation reactions are carried out at temperatures of between about 0°C to about 200°C depending on the nature of the reaction. Preferred temperatures are between about 0 ° C to about 75°C for the acylation reactions and between about 25°C to about 100°C for the alkylation reactions.
SUBSTITUTE SHEET (RULE 26) Additional compounds of formula I may be prepared by the well known reductive alkylation reaction of the compounds of formula I where R~ is -NHS with aldehydes and ketones in the presence of hydrogen gas and a platinum or palladium catalyst or in the presence of a reducing agent such as sodium cyanoborohydride.
Other compounds of formula I can be synthesized using an activated aromatic or heterocylic compound, which are either commercially available or can be produced using methods known in the art. To form the additional compounds, these reactants are reacted with compounds of formula I where Rz is OH or NHz. As shown below, the term activated aromatic or heterocycfic compound implies a ring compound of formulae VIII or IX;
SUBSTITUTE SHEET (RULE 26) ~~1~~ ~~J
-11~1-i R~ Y
R 2 w w ~ B~
+ n Re O~E~F~Rio I
I VIII
R2=OH, NHz R6 Ri R'~8~~ w w n RB/O~E~F\Rio ~ i I
1 0=0 , NH
R~12 ~Rl + _ / / Ri3 ~~ ~L Y
K
I
Ria Ix R2=OH, NH2 R~12 ,R11 ID\ _ R ~ 3 ~'~K~~ G
I
Rya 1 Q=0 , NH
SUBSTITIfff SHEET (RULE 26) ~15'~4~~
_, , ~2_ where Y is a suitable leaving group (for example halogen or trifluoromethanesulfonyloxy) and the ring is rendered susceptible to nucleophilic attack by the presence of one or more nitrogen atoms in the ring or by the presence of one or more electron withdrawing groups (in other words one or more of Ra, R" Ra, R9, R,o, R", R, 2, R, 3, or R" are halogen, -CF,, vitro, cyano, alkoxycarbonyl, amidocarbonyl, etc.) attached to the ring. Values for A, B, D, E, F, G, I, J, K, and Re, R,, Re, R9, R,o, R", R,z, R", and R" may be selected from those described previously. Solvents suitable for use with the activated aromatic or heterocylic compounds include, for example, dimethylformamide, N-methypyrrolidinone, or methylene chloride and a base (for example triethylamine, 4-dimethylaminopyridine, sodium or potassium carbonate, SUBSTITUTE SHEET (RULE 26) _, 2_ sodium hydride) may be used to facilitate the process if desired. Preferred solvents depend on the solubility of the reagents and the selection thereof would be known to one skilled in the art. These alkylation or acylation reactions are carried out nt temperatures of between about 0°C to about 200°C depending on the nature of the reaction. Preferred temperatures are between about 50°C to about 125°C for these reactions.
The alkylation and acylation procedures described above can also be useful in synthesizing of intermediates of formula V.
Compounds of formula I where Rz is one of the claimed alkyl, alkenyl, or alkynyl moieties can be prepared by reaction of compounds of formula I where Rz is CF,SO, with an appropriate olefin or acetylene compound in the presence of a palladium catalyst. The selection of appropriate olefin or acetylene depends on the alkyl, alkenyi, or alkynyl moiety desired in the end product, as would be appreciated by one skilled in the art. The alkenyl and alkynyl substituted compounds can be produced using the following reaction scheme:
Rlkene, or Rlkyne F'?=~F3S~3_ CatdlySt R1 R~=substituted or '- ~ ~ ~ unsubstituted C
alkenyl or alkynyl as ~ ~ def i ned above SUBSTITUTE SHEET (RULE 26) '~1~845~
,1_ The catalyst may be selected from those typically employed for the so-called Heck reaction (palladium acetate, palladium chloride, bis (acetonitrile) palladium chloride, for example). The reaction is carried out neat or in a reaction inert solvent such as acetonitrile, dimethyfformamide, or N-methylpyrrolidinone. The reaction is conveniently run at 20°C to 160°C, preferably 60°C to 130°C.
The details of reactions of this type have been well described in the literature (Organic Reactions 1982, 27, 345).
The synthesis of compounds having the claimed alkyl moieties require the additional step of reducing the product of the reaction discussed in the previous paragraph. The reduction is performed using standard methods known in the art.
The Heck reaction can also be useful in the synthesis of intermediates of formula V, as is known in the art.
The compounds of formulae I and intermediates of formula V where R~ is CF,SO, can be prepared by reacting the corresponding Rz substituted hydroxy SUBSTITItTE SHEET (RULE 26) t' 1~8 ~3~3 _13-compounds of formulae I or V with an activated form of trifiic acid, for example, triflic anhydride, acid chloride, N-phenyttrifluoromethanesulfonimide, preferably triflic anhydride, typically in the presence of a base, such as, for example, triethylamine or diisopropylethylamine, preferably triethylamine. The reaction may be run in an inert solvent, such as, tetrahydrofuran or methylene chloride, at a temperature of from about -78°C to about 25°C, preferably below about 0°C. This procedure is known in the art, as shown, for example, in J. Amer. Chem. Soc., 1987, 109, 5478.
A method to prepare the compounds of formula I where Rz is R, or R,(CHz)b(C=O)(CHz)~ is accomplished by reacting compounds of formula I where Rs is trimethylstannyl or tributylstannyl with an aryl or vinyl halide, or an aryl or vinyl triflate, or an aryl or alkyl acid chloride or a heteroaryl halide or triflate in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium, and is shown in the following reaction scheme:
Ri Acid Chloride, Aryl Halide or i + Tr i f l ate , He ternary l i Halide or Triflate I
',=~1e3.'-n- ,Bu3Sn-' R =R
w w R4(CH2)b(C=0)(CH2)~_ 'I where c =0 and R4 ~ ' is as defined above The procedures and conditions to carry out this reaction are known to those in the art, for example, in Angew. Chem. Int. Ed. Engl., 1986, 25, 508. . The triflate variant of this reaction is also known in the art, for example, in J. Amer. Chem.
Soc., 1987, 109, 5478. A further variation of this type of process which uses an alkyl or aryl halide in the presence of carbon monoxide gas and a palladium catalyst is also known, for example, in J. Amer. Chem. Soc., 1988, 110, 1557.
SUBSTITUTE SHEET (RULE 26) X158 ~5'~
It will be recognized by one skilled in the art that the coupling reactions described above may also be used to prepare the intermediates of formula V.
The stannane compounds I and V may be prepared from the compound I (Rz being CF,SO,) following known literature procedures (J. Amer. Chem. Soc.,1987, 109, 5478) .
A method to prepare compounds of formula I where R~ is R4 is accomplished by reacting compounds of formula I where R2 is bromo, iodo, or -OSOZCF, with an arylstannane, arylboronic acid, heteroaryl boronic acid, or heteroarylstannane in the presence of a catalyst, preferably tetrakis(triphenylphosphine)palladium, in an inert solvent, and is shown in the following scheme:
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 ~14-I
R~ , w arylstannane or ~ + heteroarylstannane -or the corresponding Rz - Br , I , or -OS02CF3 boron i c ac i ds I
R2 - Ra The procedures and conditions to cant' out this reaction are known to those skilled in the art, for example, in Angew. Chem. Int. Ed. Engl., 1986, 25, 508. The triflate variant of this reaction is also known in the art, for example, in J. Am. Chem. Soc., 1987, 109, 5478. The required arylstannanes or heteroarylstannanes are available by methods known to one skilled in the art, for example, in J. Am. Chem. Soc, 1987, 109, 5478.
The procedure and conditions for boronic acid couplings are described in J.
Org.
Chem. 1993, 58, 2208.
A method of preparing compounds of formula I and intermediates of formula V where RZ is -O-R, is to react corresponding compounds of formula I or intermediates of formula V where Rz is -OH with alcohols, for example, ethanol or benzyl alcohol, in the presence of triphenylphosphine and diethyl azodicarboxylate in a Mitsunobu reaction. Mitsunobu reactions are known in the art, for example, as disclosed in Synthesis 1981, 1.
Further compounds of formula 1 where RZ is R,-(CH~)e O-(C=O)-(CHz)~ or R4(CHZ)e NH-(C=X)-(CHZ)~ and c is 0 may be prepared by reaction of compounds of the formula I where Rz is OSOzCF, with an alcohol or an amine and carbon monoxide in the presence of a palladium catalyst. Hydrolysis of the resulting esters or amides to SUBSTITUTE SHEET (RULE 26) the corresponding acids and treatment following the general procedures outlined in EP
0 438 230 A2 further allow the preparation of additional compounds of formula I where R~ is -R, and R, is of formula XVI [e.g., a (1,2,4-oxadiazol-5-yl)-naphthalenej.
Compounds of formula I may also be prepared using standard functional group manipulations known in the art and which are disclosed in various standard synthetic chemistry texts. Examples of these are discussed below.
When RZ is R,(CH~)b(C=O)(CHz)~-, it may be reacted with a reducing agent, to yield the corresponding alcohol. Standard methods known in the art can be used.
Useful reducing agents include sodium borohydride, lithium aluminum hydride, or borane (or any of its complexes).
SUBSTITUTE SHEET (RULE 26) Compounds of formula I where the Rz substituent includes a ketone or ester carbonyl moiety may be treated with organometallic agents, such as alkyl- and nryi lithiums, or Grignard reagents using methods known in the art. In this reaction, the resulting compounds will be tertiary alcohols (Rz= -C(OH)R,RS).
When R2 contains an amide group, treatment with a reducing agent, such as, for example, lithium aluminum hydride or borane using known methods, produces the corresponding alkylated (or aralkylated) secondary or tertiary amines.
Another example of the interconversion of compounds of formula I is the reduction of a vitro group of an Rz substituent including a nitrophenyl or nitropyridyl group to the corresponding amine. For example, as shown below, r~0~ ~ R1 NH2 H R1 N w W W N w ' I i i ~ ~Z ~ i where R, and Z are as defined above, the reaction may be carried out using known vitro group reducing agents and methods, for example, hydrogenation over noble metal catalysts (palladium or platinum on a support, such as carbon, 'rf desired) or by dissolving metal reduction.
In a further example of the interconversion of the compounds of formula I, the product of the previous reaction scheme may be cyclized with, for example, dimethylformamide dimethyl acetal or methyl orthoformate to produce fused imidazole compounds of formula I, as shown below, SUBSTITUTE SHEET (RULE 26) X15845?' trialkyl orthoformate w N w w or OMF-acetal I ~Z I ~ i or diethyl ethoxymethylene malonate, or ethoxymethylene-malononitr~le to N=~ Ri N
is ~Z
The reaction may be carried out in an inert solvent, such as, for example, dimethylformamide, ethanol, or dimethyl sulfoxide, preferably dimethylformamide. The 20 reaction is run at a temperature of from about 20 °C to about 125°C. If desired, an acid catalyst, such as, p-toluenesulfonic acid or camphor sulfonic acid, preferably p-toluenesulfonic acid, may also be used to facilitate the reaction. In some cases the SUBSTITUTE SHEET (RULE 26) 5g~5'~
~1 amidine compounds of formula I can be isolated, especially when the acid catalyst is not used.
Another method to carry out the reaction shown in the previous scheme employs diethyl ethoxymethylenemalonate, ethoxymethylenemalononitrile, or related reagents preferably ethoxymethylenemalononitrile, as the cyclization reagent.
This reaction may be run in an inert solvent, such as, acetic acid, ethanol, or isopropanol, preferably isopropanol or acetic acid. The reaction temperature should be from about 25°C to about 150°C. The preferred temperature is the reflux temperature of the solvent for convenience and to decrease the reaction time.
Compounds of formula I where R, is tetrahydropyridine, piperidine, or azacycloalkylmethyl may be prepared from 8-bromo-fi-tetralone, which is known in the art, for example in U.S. Patent No. 4,897,405, as shown in the following reaction scheme:
SUBSTITUTE SHEET (RULE 26) Br ~ \
+ (PhCH~)~NH
Br Br ( PhCHz)z (PhCHz)z / \ / \
/ ~ \ /
X XI
Br BOC
~ Pr~CH2~2N
/ \
\ / /
XI SnMe3 °hC H2 ~,N~ \
\ /
I R1=Formula III
/ \ / \
\ / \ /
I R1=Formula III I R1=Formula III
SUBSTITUTE SHEET (RULE 26) The 8-bromo-fi-tetralone is first reacted with an amine, for example, dibenzylamine to form an enamine X using the same procedure disclosed previously on page 8. The enamine X can be dehydrogenated as described above on page 9, chloranil being the preferred reagent with these particular reactants, to yield 1-bromo-7-amine substituted naphthalenes XI. Selection of an appropriate amine for the enamine-forming step would be apparent to one skilled in the art, for example, diallylamine and dibenzylamines for instance. Compounds XI can be then treated with vinylstannanes, for example, 1-BOC-4-trimethylstannyl-1,2,5,&tetrahydropyridine (BOC=tert-w. X15845?' _17-butyloxycarbonyl), shown in the above scheme, in the presence of a catalyst.
Palladium is the preferred catalyst, for example (Ph,P),Pd or PdZ(dba), and the reaction follows the same procedures as described above on pages 12 to 14, where R, is tetrahydropyridine in a so-called Stille and Heck reactions.
Compounds of formula I where R, is piperidine can be prepared by catalytic hydrogenation of the tetrahydropyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon as the catalyst.
Compounds I where R, is piperidine or tetrahydropyridine can be produced, for example, by removal of the benzyl groups (when R~ is dibenzylamino) by catalytic hydrogenolysis, using a suitable catalyst such as palladium hydroxide, palladium on carbon, or platinum on carbon, preferably palladium hydroxide. The reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a erotic acid, such as acetic acid or HCI. The preferred acid is acetic acid.
In this case, the resulting compounds are of formula I where R~ is amino. The amino group can be derivatized using standard techniques known in the art and as described previously on pages 10 to 16 to afford further compounds of formula I with substituted amines.
Compounds of formula XI from the previous reaction scheme may also be treated with alkyllithium reagents, for example, butyllithium, sec-butyllithium or tert-butyllithium, preferably butyllithium in an inert solvent, as shown below, SUBSTITUTE SHEET (RULE 26) Br (PhCH2)2N /
+ Butyllithium ~ /
XI
Li (PhCH2>2N / \
\ /
XII
Fhi_H2)2N , \
\ /
~ P1=Formul a I I I OR IV
Suitable solvents include, for example, ether or tetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures range from about -110°C to about 0°C. The intermediate lithium anions of formula XII thus formed may then be further reacted with a suitable electrophile, selection of which depends on the desired substituent at the R, SUBSTITUTE SHEET (RULE 26) -1 &
position. Suitable electrophiles to prepare compounds I where R, is formula III or IV
include, for example, carbonyl derivatives or alkylating agents (e.g., 1-BOC~-piperidone, 1-BOC-prolinal or 1-FMOC-2-chloromethylpyrrolidine (FMOC=fluorenylmethoxycarbonyl)).
In the case where an aldehyde or ketone is used as the electrophile, the intermediates XIII, XIV, or XX which are formed require that the hydroxy group be removed so as to result in compounds of formula I as shown below, BOC
~ N
HO r, (PhCH2)2N , ~ (PhCH2)2 I i ~ I i XIII I R1=Formula IV
BOC
N, <>
a Pr.[H i N I
z 2 / HO \ (PhCH2)zN
I
w i w i XIV I R1=Formula III
BOC
'N
HO Ri Pr~i'H, ~,N \ CPhCH2)2N
' i w I
XX I R1=Formula V
SUBSTITUTE SHEET (RULE 26) WO 94/21619 PCT/US94/01206 -_..
2 ~. 5 8.~ 5'~ -, 8n -This step may be accomplished by one of several standard methods known in the art. For example, a thiocarbonyl derivative (for example a xanthate) may be prepared and removed by a free radical process, both of which are known to those skilled in the art. Alternatively, the hydroxyl group may be removed by reduction with SUBSTITUTE SHEET (RULE 26) -1 s.
a hydride source such as triethyisilane under acidic conditions, using such as, for example, trifluoroacotic acid or boron trifluoride. The reduction reaction can be performed neat or in a solvent, such as methylene chloride. A further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using standard methods. The leaving group is then removed with a nucleophilic hydride, such as, for example, lithium aluminum hydride. This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.
Also, a reducing agent may be used to reductively remove of the benzylic substituent.
Suitable reducing agents include, for example, Raney nickel in ethanol, or sodium or lithium in liquid ammonia. Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol XlII, XIV, or XX to an olefin with a reagent such as Burgess salt tJ. Or4. Chem., 1973, 38, 26) followed by catalytic hydrogenation of the double bond under standard conditions with a catalyst such as palladium on carbon. The alcohol may also be dehydrated to the olefin by treatment with acid such as p-toluenesutfonic acid. For Xlll the free radical procedure is preferred because it preserves the stereochemical integrity of the chiral center. For XIV or XX the Burgess salt or acid dehydration procedures are preferred.
In the case where R= is, for example, dibenzylamino, additional compounds of formula 1 may be prepared by hydrogenolysis and derivatization as described above on pages 10 to 16.
8-bromo-(3-tetralone, discussed earlier, may also be utilized to form other compounds of formula I, as shown below, * Trade-mark a 215 __ Br Br / w Br F 0..
P=H or Protecting Group w /
,5 Ri P 0-, i R1 - Formula or IV
R1 Ri Fn Rz ~w ~ / w / ~ I /
1 - Formula I R1 - Formula III or IV
I I I or I V
Rz - R40,R4, alkenyl alkynyl (substituted and unsubstituted SUBSTITUTE SHEET (RULE 26) WO 94/21619 215 8 ~ 5 7 PCT/US94/01206 8-bromo-f3-tetralone is first dehydrogenated to form 1-bromo-7-hydroxynaphthalene using an oxidizing reagent, such as, for example, elemental sulfur as described above on page 8 or N-bromosuccinimide. An appropriate protecting group is then used to protect the hydroxyl group if desired, formation and selection being w'tthin the knowledge of one skilled in the art (e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 ). This is followed by subsequent replacement of the bromo substituent using methods described previously on pages 16 to 18. After replacement of the bromo substituent, the hydroxyl protecting group may be removed using standard chemistry, and the free hydroxyl group may be derivatized as described above on pages 10 to 14 to afford compounds of formula I
wherein RZ is attached to the naphthalene ring via a carbon or oxygen atom. In some cases the protecting group may also serve as an activating group for further transformations, CF,SO, for example, as described earlier on pages 12 to 14 or may simply be the final Rz moiety.
Unless indicated othervvise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or SUBSTITUTE SHEET (RULE 26) ~15845~ -2,-acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the fomnula I which are also acidic in nature, e.g., where R~ contains a carboxylate, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particular, the sodium and potassium salts.
These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction of maximum product of yields of the desired final product.
The compounds of the formula I and the pharmaceutically acceptable salts thereof (hereinaffer, also referred to as the active compounds of the invention) are useful psychotherapeutics and are potent serotonin (5-HT, ) agonists and antagonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, chronic paroxysmal hemicrania and headache associated with vascular disorders, pain, and other disorders arising from deficient serotonergic neurotransmission such as Alzheimer's disease. The compounds can also be used as centrally acting antihypertensives and vasodilators.
The affinities of the compounds of this invention for the various serotonin 1 receptors are evaluated using standard radioligand binding assays as described in the literature. The 5-HT,A affinity is measured using the procedure of Hoyer et al. (Brain Res., 1986, 376, 85). The 5-HT,~ affinity is measured using the procedure of Pazos et SUBSTITUTE SHEET (RULE 26) 2158 ~5~' al. (Eur. J. Pharmacol., 1985, 106, 539). The 5-HT,o affinity is measured using the procedure of Heuring and Peroutka (J. Neurosci., 1987, 7, 894).
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pham~aceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.
almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbid acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
SUBSTITUTE SHEET (RULE 26~
'~1~8 ~~~ -23-The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., migraine) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or ~puff" of aerosol contains 20Ng to 1000Ng of the compound of the invention.
The overall daily dose with an aerosol will be within the range 100Ng to 10 mg.
Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million (a) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF
refers to dimethylformamide. Chromatography refers to column chromatography performed using 32-63 Nm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25°C. All non-aqueous SUBSTITUTE SHEET (RULE 26) reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure implies the use of a rotary evaporator.
The terms 1-piperazinyl and piperazin-1-yl, t-piperidinyl and piperidin-1-yl, and 3-pyrrolidinyl and pyrrolidin-3-yl are used interchangeably throughout this document.
Triflate refers to -OSOzCF3 or CF,SO~.
SUBS?ITUTE SHEET (RULE 26) Example 1 7-Benzamido-1-14-methyl-1-piperazinyl)-naphthalene 7-Amino-a-tetralone (42.15 g, 0.262 mol) was dissolved in dry THF (1000 mL) and triethylamine (38.3 mL, 0.288 mol) was added. The mixture was chilled to 0°C and benzoyl chloride (33.4 mL, 0.288 mol) was added dropwise with a THF (10 mL) rinse.
The mixture was mechanically stirred overnight, then the solvent was removed with a nitrogen stream. The residues were taken up in methylene chloride and extracted with 1 N HCI, water, saturated sodium bicarbonate, and brine. The organic phase was further dried over calcium sulfate and concentrated to a solid mass.
Recrystallization from ethanol (650 mL) yielded 52 g of 7-benzamido-a-tetralone. Concentration of the mother liquors yielded another 6 g for a total yield of 58.9 g (8596): mp 153-156°C.
Analysis calculated for C"H"NOz: C, 77.25; H, 5.34; N, 5.30. Found: C, 77.05;
H, 5.57; N, 5.30.
7-Benzamido-a-tetralone (5.0 g, 18.95 mmol) was dissolved in dry THF (107 mL) and N-methyl-piperazine (6.3 mL, 56.8 mmol) was added. The solution was cooled to -78°C and titanium tetrachloride (2.5 mL, 22.75 mmol) in methylene chloride (30 mL) was added dropwise. The mixture was stirred overnight and during this time a fine green precipitate formed. The solvent was removed under a stream of nitrogen and the residue was stirred vigorously in a mixture of ethyl acetate and 5N ammonium hydroxide for 2 hours. The solid which formed was collected, washed with ethyl acetate and then ether, and dried in vacuo. The filtrate was discarded. The solid was vigorously stirred with 1 N sodium hydroxide (100 mL) and methylene chloride (100 mL) for 2 hours. The solid which did not dissolve was removed by filtration. The phases were separated from the filtrate and the organic layer was washed with brine, dried over calcium sulfate and concentrated to give 1.01 g of product. The solid was now stirred with dimethyl sulfoxide (DMSO, 150 mL) for 2 hours and filtered again. The undissolved material was discarded. The DMSO was removed at reduced pressure and the residue was taken up in methylene chloride. This organic solution was treated with brine which removed the last traces of DMSO from the organic phase and caused immediate precipitation of 2.29 g more product which was collected and dried. The phases were separated from the filtrate. The organic layer was dried over sodium sulfate and concentrated to leave 2.13 g of light tan solid product. In this fashion 5.43 g, 83°~6 of 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalenewas obtained; 'H
NMR
SUBSTITUTE SHEET (RULE 26) 15~~57 (CDC1~) d 7.88 (dd, J = 1.5, 8 Hz, 2H), 7.77 (br s, 1 f-(), 7.59 (d, J = 2 Hz, 1 H), 7.56-7.46 (m, 4H), 7.16 (d, J = 8 Hz, 1 H), 5.32 (t, J = 4.5 Hz, 1 H), 2.88 (br s, 4H), 2.69-2.55 (m, 6H), 2.36 (s, 3H), 2.27-2.17 (m, 2H).
A mixture of xylene (500 mL) and 10 96 Palladium on carbon (2.0 g) was refluxed overnight with azeotropic removal of water by means of a Dean-Stark trap containing 4 ~ molecular sieves. The mixture was cooled to room temperature and 7-benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene (5.44 g, 15.67 mmol) was added. The mixture was heated at reflux for 2 hours, cooled, and filtered through a Celite pad. The filtrate was concentrated in vacuo and purified by silica gel flash chromatography (1.5 1 O x 4 inches). Elution with 50 to 8596 ethyl acetate/hexane gave 7-benzamido-a-tetralone (0.636 g). Continued elution with 9596 ethyl acetate / hexane and pure ethyl acetate gave 1.37 g of title product followed by 1.95 g of a 2:1 mixture of title product and 7-benzamido-1-(4-methylpiperazinyl)-1,2,3,4-tetrahydronaphthalene. The 1.95 g mixture was rechromatographed as above to yield 1.0 g more pure title product. In this manner 2.37 g, 4396 was obtained: mp 173-175°C. Analysis calculated for C~~H1~N,0: C, 76.49; H, 6.71; N, 12.16. Found: C, 75.94; H, 6.39; N, 11.95.
Exnmole 2 7-Amino-1-(4-methyl-1-piperazinyll-naphthalene 7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene (the product from example 1, 3.75 g, 10.87 mmol) was slurried in 6N HC) (a mixture of concentrated HCI
(25 mL) and ethanol (25 mL)) (50 mL) and refluxed for 3.5 hours. The mixture was cooled and brought to pH 10 with 1 N sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over calcium sulfate and concentrated to afford 2.44 g (92 96) of the title product which was suitable for use in further reactions without purification. A sample was recrystallized from isopropyl alcohol for analysis: mp 157-159°C; 'H NMR a 7.G5 (d, J = 8.5 Hz, 11i), 7.44 (d, J = 8 Hz, 1 ti), 7.35 (d, J = 2 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 I-i), 7.04 (d with long range coupling, J = 7 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 )i), 3.88 (br s, 3H), 3.12 (br s, 4H), 2.42 (s, 3H). Analysis calculated for C,SH,9N,: C, 74.65; H, 7.94; N, 17.41.
Found: C, 74.79; H, 8.14; N, 17.41.
*Trade-mark ,._ Example 3 7-(2-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene A solution of 7-amino-t-(4-methyl-1-piperazinyt)-naphthalene (0.197 g, 0.817 mmol) and triethylamine (0.217 mL, 1.63 mmol) in acetonitrile (10 mL) was chilled to 0°C and 2-naphthoyl chloride (0.311 g, 1.63 mmol) was added. The solution was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The mixture was stirred vigorously with saturated sodium bicarbonate for 2 hours and the phases were separated. The organic Isyer was dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1 x 3 inches). Ethyl acetate/hexane gradient elution of from 25:75 to 75:25 followed by ethyl acetate and finally 596 ethanol/ethyl acetate gave 0.31 g of light yellow foam. Trituration with hexane yielded 0.235 g (7296) of the title product as an amorphous solid: mp 95-130°C. High resolution mass Spectrum (HRMS) m/e calculated for CzaHz5N30: 395.1994. Observed m/e: 395.1981.
Example 4 7-(3-Nitrobenzamido)-1-(4-methyl-1-piaerazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3-nitrobenzoyl chloride (0.127 mL, 0.684 mmot) in acetonitrile (10 mL) with an overnight reflux. The product was purified by silica gel flash chromatography followed by recrystallization from ethyl acetate to yield 0.116 g (4796) of the title product: mp 182-184°C. Analysis calculated for CZ~H~~N,O,:
C, 67.68; H, 5.68; N, 14.35. Found: C, 67.47; H, 5.64; N, 14.08.
Example 5 7-~1-Naphthylcarboxamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.227 g, 0.94 mmol) and triethylamine (0.133 mL, 0.1.32 mmol) and 1-naphthalenecarboxylic acid chloride (0.25 g, 1.32 mmol) in acetonitrile (10 mL) with stirring overnight at room temperature. The product was purified and after chromatography and recrystallization from ethyl acetate yielded 0.213 g (5796) of the title compound and had; mp 217-218°C. Analysis calculated for C~aH~5N,0: C, 78.96, H, 6.37; N, 10.62. Found: C, 78.66; H, 6.33; N, 10.48.
SUBSTITUTE SHEET (RULE 26) Example 6 7-(3-Chlorobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.0768 (2096) of the title compound: mp 147-148°C. HRMS m/e calculated for CZZH=zCIN~O: 379.1448. Observed m/e:
379.14473. Analysis calculated for Cz~Hz~CIN,O: C, 69.56; H, 5.84; N, 11.06.
Found:
C, 68.95; H, 5.81; N, 10.96.
Example 7 7-(3 5-Dinitrobenzamidol-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 3 from 7 amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from acetonitrile to yield 0.17 g (6396) of the title compound: mp 254-256°C. Analysis calculated for C~~Hz,Ns05: C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Example 8 7-(4-Chlorobenzamidol-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride (0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from ethyl acetate to yield 0.17 g (4396) of the title compound as a white solid mp 174-175°C. HRMS m/e calculated for CzzHZ2CIN30:
379.1448. Observed m/e: 379.1465. Analysis calculated for CzzHzzCIN30: C, 69.56;
H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
SUBSTITUTE SHEET (RULE 26) s ~,1 Example 9 7-(3-Cyanobenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.213 g, 0.883 mmol) and triethylamine (0.258 mL, 1.94 mmol) and 3-cyanobenzoyl chloride (0.322 g, 1.94 mmol) in acetonitrile (10 mL) with stirring at reflux for 2 hours and then at room temperature overnight. The mixture was concentrated and the residue was taken up in methylene chloride.
This organic solution was washed with 0.5 N sodium hydroxide, dried over calcium sulfate and concentrated. The product was isolated by silica gel flash chromatography and recrystallization from isopropyl alcohol to yield 0.184 g of (6096) of the title compound:
mp 220-222°C. Analysis calculated for CZ,HZZN,O: C, 74.57; H, 5.99; N, 15.12.
Found: C, 74.42; H, 5.78; N, 14.96.
Example 10 7-(4-Hydroxvbenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.118 g, 0.489 mmol) and triethylamine (0.13 mL, 0.98 mmol) in acetonitrile (10 mL) was chilled to 0°C
and 4-triisopropylsilyloxybenzoyl chloride (0.16 g, 0.51 mmol) dissolved in methylene chloride was added all at once. The mixture was gently refluxed overnight;
then 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.038 g, 0.16 mmol), 4-triisopropylsilyloxybenzoyl chloride (0.5 g, 1.6 mmol), and triethylamine (0.13 mL, 0.93 mmol) were added. The reaction was refluxed for an additional 24 hours, cooled and the solvent was removed at reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and stirred vigorously for 5 hours. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1 x 3.5 inches). Elution with 2596 ethyl acetate/hexane removed unweighed recovered acid chloride. Continued elution with an ethyl acetate/hexane gradient of from 1:3 to 3:1 followed by 10096 ethyl acetate gave 0.238 g of 7-(4-triisopropylsilyloxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene as a viscous tan oil.
The product of the above reaction was dissolved in dry THF (10 mL) and tetrabutylammonium fluoride (0.47 mL, 0.47 mmol, 1 M in THF solution) was added dropwise. The solution darkened and was stirred 2 hours followed by addition of 0.2 SUBSTITUTE SHEET (RULE 26) mL more tetrabutylammonium fluoride. After stirring an additional 3 hours, the solvent was removed and the residue was taken up in ethyl acetate. This organic phase was washed with water and brine, dried over calcium sulfate and concentrated to a white foam. This foam was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with ethyl acetate/hexane of from 1:3 to 3:1 gave nil. Continued elution with 5%
ethanol/ethyl acetate gave first the title product (0.04 g) which was about 80 % pure followed by an additional 0.02 g of pure product. The 0.02 g sample was triturated with ether / hexane and yielded 0.006 g (1.9%) of title product as a tan solid: mp 160°C. HRMS m/e calculated for CzzHz3N~0~: 361.1789. Observed m/e:
361.1787.
1 p Example 11 7-Benzamido-1-( 1-aiperazinyll-naphthalene The title product from Example 1 (0.50 g, 1.45 mmol) was dissolved in methylene chloride (10 mL) and chilled to 0°C. 1-chloroethyl chloroformate (0.156 mL, 1.45 mmol) was added via syringe. The mixture was allowed to come to room temperature and then refluxed 3 hours. Additional 1-chloroethyl chloroformate (0.1 mL, 0.93 mmol) was added and the mixture was further refluxed overnight. Methanol (tOmL) was added and the reaction was refluxed for 2 hours. The mixture was concentrated and the residue was taken up in methylene chloride and extracted with 1 N NaOH and brine. The organic phase was dried, concentrated onto silica gel, and flash chromatographed (1 x 4 inches silica gel). Gradient elution with ethyl acetate /
hexane of from 1:1 to 10096 ethyl acetate followed by elution with 2 to 10 96 ethanol/0.1 ammonium hydroxide/ethyl acetate gave recovered unweighed starting material.
Continued elution with 15% methanol / 0.1 % ammonium hydroxide/ethyl acetate gave 0.32 g of the title product as a clear colorless oil which partially crystallized on standing.
Trituration with ether gave 0.13 g (2796) of the title compound as white crystals: mp 141.5-144°C; 'H NMR a 8.58 (br s, 1H), 8.04 (br s, 1H), 7.95 (dd, J =
8, 1.5 Hz, 2H), 7.84 (d, -J = 9 Hz, 1 H), 7.68 (dd, J = 2, 9 Hz, 1 H), 7.62-7.49 (m, 4H), 7.37 (t, J = 8 Hz, 1 H), 7.12 (d, J = 7 Hz, 1 H), 3.32-3.22 (m, 5H), 3.16 (br s, 3H), 2.40 (br s, 1 H, exchanges with DSO). HRMS m/e calculated for C~,Hz,N30: 331.1680. Observed m/e:
331.1682.
SUBSTITUTE SHEET (RULE 26) Example 12 7-(4-Chlorobenzamido-1-(1-piperaziny~-naphthalene The title product of example 8 (1.69 g, 4.62 mmol) and 1,8-bis (dimethylamino)naphthalene (3.47 g, 16.2 mmol) were dissolved in dichloroethane (160 mL) and chilled to 0°C. 1-Chloroethyl chloroformate (0.8 mL, 7.4 mmol) was added and the solution was refluxed overnight. The mixture was concentrated and flash chromatographed on silica get (2 x 3 inches). Elution with 10 to 2596 ethyl acetate /
hexane gave first an unweighed impurities and then 1.56 g of a mixture of 1,8-bis (dimethylamino)naphthalene and the urethane intermediate (1:1.2 ratio). The mixture was dissolved in methylene chloride and extracted repeatedly with pH 5.8 buffer. The organic layer was dried over calcium sulfate and concentrated to give 0.98g of base free intermediate urethane suitable for subsequent reaction.
The intermediate was dissolved in methanol (40 mL) and refluxed 5 hours. The mixture was concentrated and the residues were taken up in methylene chloride.
The organic phase was washed with 0.5 N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1 x 2 inches).
Elution with 5 to 1596 methanol/0.19o ammonium hydroxide/ethyl acetate gave 0.667 g of oily solid. This semi-solid recrystallized from methanol to give 0.54 g (3296) of the title compound as tan crystals in hero crops: mp 210-211 °C. HRMS m/e calculated for Cz, H~°CIN~O: 365.1290. Observed m/e: 365.1294.
Example 13 7-(1-Naphthylmethylamino)-1-(4-methyl-1-piperazinyl)-naphthalene To a cold (-78°C) mixture of lithium aluminum hydride (0.012 g, 0.316 mmol) in THF (5 mL) was added the product of example 5 (0.10 g, 0.256 mmol) all at once. The mixture was allowed to warm to ambient temperature and stir 5 hours. The mixture was refluxed overnight. The mixture was cooled to 0°C and additional lithium aluminum hydride (0.014 g, 0.368 mmol) was added and the mixture was refluxed 5 hours more.
The mixture was again cooled to 0°C and carefully quenched with water and the solvent was removed. The residue was taken up in ethyl acetate, dried over sodium sulfate, concentrated, and flash chromatographed on silica gel (1 x 2.5 inches).
Elution with a gradient of 50 to 85% ethyl acetate/hexane gave 0.05 g of title product.
Recrystallization from ether gave 0.018 g (18.596) of title product as a white solid: mp 140-141 °C. HRMS m/e calculated for CzeH~,N3: 381.2199. Observed m/e:
381.2217.
SUBSTITUTE SHEET (RULE 26) ~2- 215857 Example 14 7-(Benzylamino)-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 1 (0.12 g, 0.348 mmol) was dissolved in toluene (4 mL) and borane-dimethyl sulfide (0.3 mL, 3 mmol) was added. The mixture was refluxed 3 hours and cooled. 6 N HCI and ethyl acetate were added and the mixture was refluxed until all the solids had dissolved. The organic phase was separated and discarded. The aqueous phase was made basic with 4 N NaOH and extracted with methylene chloride. This organic phase was washed with brine, dried over calcium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (0.5 x 4 inches). Elution with 5096 and then 7596 ethyl acetate/hexane gave 0.053 g of product. This material was further purified by trituration with hexane to provide 0.03 g, (26 96) of the title product as a tan powder: mp 115-117°C; 'H NMR
a 7.64 (d, J = 8.5 Hz, 1 H), 7.46-7.24 (m, 6H), 7.14 (t, J = 7.5 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 7.00 (ss, J = 1, 7.5 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 H), 4.50 (br s, 2H), 4.34 (br m, 1 H), 3.01 (br s, 4H), 2.53 (br s, 4H), 2.38 (s, 3H). Analysis calculated for C~~Hz5N3~0.5 HzO: C, 77.61; H, 7.70; N, 12.34. Found: C, 77.78; H, 7.48; N, 12.07.
Example 15 7-Trifluoroacetamido-1-(4-methyl-1-piaerazinyl)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g,1.04 mmol) and triethylamine (0.15 mL, 1.14 mmol) in dry THF was chilled to 0°C
and treated with trifluoroacetic anhydride (0.16 mL, 1.14 mmol). The mixture was allowed to warm to ambient temperature and stir overnight. Triethylamine (0.25 mL, 1.88 mmol) and trifluoroacetic anhydride (0.16 mL, 1.14 mmol) were added and the solution was stirred another 24 hours. Triethylamine (0.15 mL, 1.14 mmol) was added and the solution was stirred 2 hours more. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was washed with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated.
The product was purified by silica gel flash chromatography (1 x 2 inches).
Ethyl acetate/hexane gradient elution of from 1:1 to 3:1 gave 0.15 g of oily product.
Trituration with hexane gave 0.11 g (3196) of the title product. A sample recrystallized from methyl cyclohexane was submitted for analysis: mp 159-160°C. HRMS
m/e calculated for C"H,eF3N30: 337.1400. Observed m/e: 337.13867. Analysis calculated for C"H,BF,N,O: C, 60.53; H, 5.38; N, 12.46. Found: C, 60.04; H, 5.27; N, 12.05.
SUBSTITUTE SHEET (RULE 26) Example 16 7-Acetamido-1-(4-methyl-1-piperazinyi)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.238 g, 0.986 mmol) and triethylamine (0.144 mL, 1.08 mmol) in acetonitrile (12 mL) was chilled to 0°C and acetyl chloride (0.077 mL, 1.08 mmol) was added all at once.
The mixture was heated to reflux for 7 hours and cooled to room temperature. (TLC with methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated to a light tan solid (0.115 g).
Trituration with hexane gave 0.09 g (3396) of the title product as a tan solid: mp 173-177°C. A
sample recrystallized from ethyl acetate was submitted for analysis: mp 177-180°C.
HRMS m/e calculated for C"H~,N30: 283.1682. Observed m/e: 283.1678.
Example 17 7-Hexanamido-1-(4-methyl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 16 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.182 g, 0.755 mmol) and triethylamine (0.201 mL, 1.51 mmol) and hexanoyl chloride (0.211 mL, 1.51 mmol) in acetonitrile (10 mL) with an overnight reflux. The product was purified by recrystallization from ethyl acetate/hexane to yield 0.0978 (3796) of the title compound: mp 144-146°C. Analysis calculated for Cz, H~9N,0: C, 74.30; H, 8.61; N, 12.38. Found: C, 73.91; H, 8.52; N, 12.22.
Example 18 7- (p-Toluenesulfonamido)-1-(4- methyl-1-piperazinyl)-naphthalene A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.205 g, 0.85 mmol) and triethylamine (0.124 mL, 0.935 mmol) in dry THF (3 mL) was chilled to 0°C
and para toluenesulfonyl chloride (0.178 g, 0.935 mmol) was added all at once.
The mixture was allowed to warm to room temperature and stirred overnight (TLC
with 40%
methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated. Flash chromatography on silica gel (1 x 3 inches) with ethyl acetate/hexane gradient elution of from 5096 to 10096 gave 0.21 g SUBSTITUTE SHEET (RULE 26) 2I584~?
of a light tan solid. The solid was further purified by two recrystallizations from ethyl acetate to yield 0.07 g (2096) of the title product: mp 180-181.5°C.
Analysis calculated for C~~HzSN,OzS: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.55; H, 6.31; N, 10.20.
Example 19 7-(Phenylaminocarbonylamino)-1-(4-methyl-1-piperazinyl)-naphthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.216 g, 0.896 mmol) and phenyl isocyanate (0.222 g, 1.86 mmol) were combined in acetonitrile (14 mL) and refluxed overnight. Phenyl isocyanate (0.106 g, 0.896 mmol) was added and the reaction was refluxed 2 hours more. Upon cooling a tan solid precipitated which was collected and recrystallized ftom methanol/ethyl acetate to give 0.202 g (62%) of the title product; mp 213-214°C. Analysis calculated for Cz~Hz,N,O: C, 73.31; H, 6.71; N, 15.54. Found: C, 73.03; H, 6.55; N, 15.22.
Example 20 7-(Benzvloxycarbonvlamino)-1-~4-methyl-1-piperazinyl)-nachthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate (0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol) was added and the reaction was stirred 5 hours more. The reaction was diluted with methylene chloride and the phases were separated.
The organic layer was washed with brine, dried over calcium sulfate and concentrated to a brown oil which was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with ethyl acetate/hexane of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 596 to 1096 gave 0.29 g of a brown foam.
This residue was recrystallized from ethyl acetate to give 0.095 g (2796) of the title product in two crops; mp 143-144°C. Analysis calculated for Cz,H15N302: C, 73.58; H, 6.71;
N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Example 21 7-((2-Benzyloxycarbonylamino)-acetamidol-1-(4-methyl-1-piperazinyl)-naphthalene N-benzyloxycarbonylglycine (0.69 g, 3.32 mmol) was dissolved in methylene chloride (10 mL) and carbonyl diimidazole (0.54 g, 3.32 mmol) was added. The solution was stirred for 2 hours; then 7-amino-1-(4-methyl-1-piperizinyl)-naphthalene (0.2 SUBSTITUTE SHEET (RULE 26) WO 94!21619 PCT/US94I01206 :-35-g, 0.83 mmol) was added. The solution was stirred overnight. The reaction was extracted with saturated aqueous potassium carbonate and brine, dried over calcium sulfate and concentrated to give white crystals. Recrystallization from ethyl acetate gave 0.187 g (52 96) of the title product as white crystals: mp 187-188°C. Analysis calculated for C~5Hz8N,0,: C, 69.42; H, 6.52; N, 12.95. Found: C, 69.21; H, 6.50; N, 12.79.
Example 22 7-(Benzoylaminothiocarbonylamino?-1-(4-methyl-1-aiperazinyl)-naphthalene To a mixture of ammonium thiocyanate (0.376 g, 4.94 mmol) in acetone (5 mL) was added benzoyl chloride (0.57 mL, 4.94 mmol) dropwise. The mixture (white precipitate) was refluxed 45 minutes which resulted in a yellow heterogeneous solution.
A solution of 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (1.0 g, 4.14 mmol) in acetone (25 mL) was added dropwise (10 mL acetone rinse also added). The mixture was refluxed 4 hours and allowed to stir overnight at ambient temperature. The mixture was concentrated onto silica gel and flash chromatographed (2 x 3.5 inches).
Gradient elution with ethyl acetate/hexane of from 5096 to 10096 gave an unweighed forerun.
Continued gradient elution with 10 to 4096 ethanol/ethyl acetate gave 1.3 g (7796) of title product as a yellow foam which was suitable for use without further purification. The compound was found to slowly decompose at room temperature. A sample recrystallized from ethyl acetate/methylene chloride for analysis: mp 160-250°C. 'H
NMR (DMSOde, D20) a 8.74 (s, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.91 (d, J = 9 Hz, 1 H), 7.70-7.51 (m, 5H), 7.42 (t, J = 8 Hz, 1 H), 7.12 (d, J = 7 Hz, 1 H), 3.11 (m, 4H), 2.79 (br s, 4H), 2.39 (s, 3H). HRMS m/e calculated for Cz,H~,N,OS: 404.1661. Observed m/e:
404.1633.
Example 23 7-(Aminothiocarbonylamino]-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 22 (1.09 g, 2.7 mmol) was slurried in ethanol (10 mL) and a solution of 1.4 g NaOH in water (14 mL) was added. The mixture was refluxed 3 hours; then the ethanol was removed with a stream of nitrogen. The aqueous residue was extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, and concentrated to leave 0.39 g (4896) of the title product. A sample was recrystallized from acetonitrile for analysis: mp 194-SUBSTITUTE SHEET (RULE 26) 195°C. Analysis calculated for C,eHz°N,S~CH,CN~0.5 HzO: C, 62.96; H, 6.67; N, 19.32. Found: C, 62.86; H, 6.71; N, 19.69.
Exempla 24 4-Benzyl-2-(-1-(4-methyl-1-piperazinyl)-7-naphthylaminol-thiazole A mixture of the title product of example 23 (0.225 g, 0.75 mmol) and 1-chloro-phenylacetone (0.188 g, 1.12 mmol) in isopropanol (6 mL) was refluxed 3 hours.
The solvent was removed and the residue was taken up in methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over calcium sulfate, and concentrated onto silica gel for flash chromatography (1 x 3 inches). Gradient elution with 5096 to 10096 ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.283 g of a yellow foam.
Trituration with ethyl acetate gave 0.137 g (4496) of the title product as yellow crystals: mp 157-160°C. Analysis calculated for CzSH~eN,S: C, 72.43; H, 6.32; N, 13.51.
Found: C, 72.55; H, 6.51; N, 13.72.
Example 25 7-(3-Nitro-2-pvridinvlaminol-1-(4-methyl-1-p~erazinyl)-naphthalene 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.2478,1.02 mmol), 2-chloro-3-nitropyridine (0.325 g, 2.05 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were combined in dry DMF (0.15 mL). The solution was refluxed 4 hours then 0.5 mL
more DMF was added and the mixture was allowed to stir at ambient temperature overnight. 2-Chloro-3-nitropyridine (0.105 g, 0.69 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were added and the mixture was refluxed 2 hours more. The solvent was removed in vacuo and the residue was taken up in methylene chloride.
This organic phase was washed with 0.5 N sodium hydroxide and brine; then it was dried over calcium sulfate and concentrated to a red oil which was flash chromatographed on silica gel (1 x 4 inches). Gradient elution with 5096 to 759'o ethyl acetate/hexane followed by elution with 10096 ethyl acetate gave a dark colored oil which crystallized upon addition of ether (2 mL) to yield 0.19 g (5196) as a dark red solid: mp 127.5-129°C. Analysis calculated for C~°Hz,N50Z: C, 66.10; H, 5.82; N, 19.27.
Found: C, 66.04; H, 5.81; N, 19.02.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ PCT/US94/01206 ~7-Example 26 7~2.4-Din'ttrophenylamino~-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.05 g, 0.207 mmol) and 2,4-dinitrochlorobenzene (0.75 g, 0.373 mmol) in dry DMF (2 mL) was refluxed 2 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to give 0.0458 (5496) of the title compound: mp 153-154°C. Analysis calculated for Cz, HZ, N50,: C, 61.91; H, 5.20; N, 17.19. Found: C, 61.42; H, 5.10; N, 16.79.
Example 27 7-(5-Nitro-2-pyridylamino)-1-(4-methyl-1-piperazinyl)-naphthalene A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.212 g, 0.88 mmol), 5-vitro-2-chloropyridine (0.314 g, 1.98 mmol), and 4-dimethylaminopyridine (0.085 g, 0.7 mmol) in dry DMF (2 mL) was refluxed 8 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated 0.5 N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with from 5096 to 9096 ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.136 g of orange oil.
Recrystallization from isopropanol followed by recrystallization from nitromethane gave 0.005 g (1.496) of the title product as orange crystals: mp 121-125°C.
Analysis calculated for Cz°HZ,NSOz~HzO: C, 62.98; H, 6.08; N, 18.36. Found: C, 62.86; H, 5.84;
N, 18.13.
Example 28 7-(2-Nitrophenylaminol-1-(4-methyl-1-piperazinyl)-naphthalene The title product was obtained following the procedure of example 27 by reacting 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.93 mmol), fluoronitrobenzene (0.255 g, 1.8 mmol), and 4-dimethylaminopyridine (0.167 g, 1.37 mmol) in dry DMF (5 mL) with an overnight reflux. The product was isolated by silica gel flash chromatography and recrystallization from ethyl acetate/ether to yield 0.0248 (796) of the title compound as orange crystals: mp 87-94°C; 'H NMR a 9.70 (br s, 1 H), 8.26 (dd, J = 1.5, 8.5 Hz, 1 H), 8.07 (d, J = 2 Hz, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 7.57 (s, J = 8 Hz, 1 H), 7.44-7.32 9m, 4H), 7.16 (dd, J = 1, 7.5 Hz, 1 H), 6.82 (dd, J = 2, 6.5, SUBSTITUTE SHEET (RULE 26) 21.58~r57 8.5 Hz, 1 H), 3.15 (br s, 4H), 2.T0 (br s, 4H), 2.41 (s, 3H). HRMS m/e calculated for C~,H,~N,O=: 362.1738. Observed m/e: 362.1736.
example 29 7-(3-Amino-2-pyridylamino~-1-(4-methyl-1-piperazinylL-naphthalene To a slurry of 1096 palladium on carbon (0.56 g) in ethanol (30 ml-a was added the title product from example 25 (3.38 g, 9.3 mmol) was dissolved in a mixture of ethanol (20 mL), methanol (50 mL), and ethyl acetate (100 mL). The mixture was hydrogenated a1 50 psi for 3 hours. A total of 36 psl of Hi was taken up (35 psi is theory). The mixture was filtered through C elite and the titter pad was rinsed well with ethyl acetate. The filtrate was concentrated to give 3.4 g (10096) of brown crystals which was an ethanolate of the title product which was suitable for further reaction without purification. A sample recrystallized from ethanol for analysis: mp 198-200°C.
Analysis calculated for Cz°H~~NS: C, 72.04; H, 6.95; N, 21.00. Found:
C, 71.72; H, 6.87; N, 20.84.
Exnmple 30 7-f 3-Benzamido-2-pvridvtamino)-1-(4-methY(-1-piperazinyt)-naphthalene The title product from example 29 (0.2 g, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) were dissolved in THF (8 mL) and the solution was chilled to 0°C. Benzoyl chloride (0.09 mL, 0.78 mmol) was added and the mixture was stirred 24 hours at room temperature. The solvent was removed and the residue was taken up in methylene chloride. The organic phase was washed with 1 N NaOH and brine; then it was dried through phase separating paper and concentrated onto silica gel for flash chromatography (1 x 3.5 inches). Elution wish methyfene chloride then 396 methanol/methylene chloride was not productive. Continued elution with 696 methanol/methylene chloride gave first 0.108 g of an impurity and second 0.128 g of product as a tan foam. The foam was further purified by recrystallization from ethyl acetate to yield 0.078 g (3096) of the title product as tan crystals: mp 205-207 ° C.
6W alysis calculated for C?,Hz,N50: C; 74.12; H, 6.22; N, 16.01. Found: C, 73.59; Fi, 5.93; N, 15.54.
Example 31 7-(3-Acetamido-2-pyridylaminol-1-(4-methyl-1-piperazinyl)-naphthalene The title compound was prepared following the procedure of example 30 from ttie product o1 example 29 (0.25 g, 0.75 mmol), acetyl chloride (0.045 mL, 0.80 rmnol) *Trade-mark and triethylamine (0.11 mL, 0.803 mmol) in tetrahydrofuran (8 mL) with stirring at room temperature for 3 hours. The product was isolated by flash chromatography and recrystallization from methylene chloride to yield 0.18g (6496) of the title compound: mp 110-114 ° C (dec.). ' H NMR (DMSOda) a 9.47 (s, 1 H), 8.65 (d, J = 1.5 Hz, 1 H), 8.35 (s, 1 H), _8.03 (dd, J = 1.5, 5 Hz, 1 H), 7.77-7.70 (m, 2H), 7.53 (dd, J = 2, 9 Hz, 1 H), 7.46 (d, _J = 8 Hz, 1 H), 7.22 (t, J = 8 Hz, 1 H), 7.00 (d, J = 7.5 Hz, 1 H), 6.88 (dd, J = 5, 8 Hz, 1 H), 3.07 (br s, 4H), 2.63 (br s, 4H), 2.29 (s, 3H), 2.14 (s, 3H). HRMS
m/e calculated for CzzH~5Ns0: 375.2054. Observed m/e: 375.2023.
Examele 32 1-(4-Methyl-1-piperazinvll-7-( 1-pyridotriazolol-naphthalene The title product from example 29 (0.219 g, 0.657 mmol) was dissolved in 5 9'0 sulfuric acid (1.5 mL) and chilled to 0°C. Sodium nitrite (0.048 g, 0.69 mmol) was dissolved in water (0.25 mL) and added dropwise with a water rinse (2 x 0.25 mL). The mixture was allowed to stir overnight. The reaction was poured onto ice and neutralized with 1 N NaOH. The aqueous mixture was extracted 3 times with methylene chloride and the combined organic layer was washed with saturated sodium bicarbonate and brine. The organic phase was dried through phase separating paper and concentrated to a brown foam. The foam was recrystallized from methanol to afford 0.124 g (5596) of the title product as tan crystals: mp 162-164°C. 'H NMR a 9.28 (d, J = 2 Hz, 1 H), 8.82 (dd, J = 1.5, 4.5 Hz, 1 H), 8.52 (dd, J = 1.5, 8.5 Hz, 1 H), 8.39 (dd, J = 2, 9 Hz, 1 H), 8.05 (d, J = 9 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.52-7.45 (m, 2H), 7.19 (d, J = 7.5 Hz, 1 H), 3.27 (br s, 4H), 2.80 (br s, 4H), 2.45 (s, 3H).
Analysis calculated for CZOHzoNe: C, 69.75; H, 5.85; N, 24.40. Found: C, 69.69; H, 5.72; N, 24.15.
Example 33 7-(Imidazol-2-ono-f4.5-blpvridin-1-yl)-1-(4-methyl-1-piperazinyl)naphthalene A mixture of the title product of example 29 (0.260 g, 0.78 mmol) and triethylamine (0.21 mL, 1.56 mmol) in methylene chloride (12 mL) was chilled to 0°C
and triphosgene (0.09 g, 0.30 mmol) was added all at once. The mixture became homogeneous and was stirred overnight at ambient temperature. Additional triphosgene (0.02 g, 0.07 mmol) was added and the mixture was stirred 4 hours more.
Saturated sodium bicarbonate was added and the reaction was stirred 30 minutes to decompose any unreacted triphosgene. The phases were separated and the organic SUBSTITUTE SHEET (RULE 26~
2I584~~
~0-layer was washed with brine and dried through phase separating paper. The solution was concentrated and flash chromatographed on silica gel (1 x 4 inches).
Gradient elution with hom 6096 to 10096 methylene chloride/hexane was not productive.
Continued elution with a gradient of from 2 to 496 methanol/methylene chloride gave 0.032 g of an oil which was discarded. Further elution with a gradient of 4 to methanol/methylene chloride gave 0.23 g of crystalline solid product. The solid was triturated with methylene chloride and filtered to afford 0.079 g (2896) of the title product as a white powder: mp 260-262°C (dec.). 'H NMR (DMSOda) 6 11.44 (br s, 1H), 8.49 (d, J = 1.5 Hz, 1 H), 8.01 (d, J = 9 Hz, 1 H), 7.97 (dd, J = 1.5, 5 Hz, 1 H), 7.86 (dd, J
= 2, 9 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7.49-7.42 (m, 2H), 7.16-7.11 (m, 2H), 3.10 (br s, 4H), 2.58 (br s, 4H), 2.25 (s, 3H). HRMS m/e calculated for CZ, Hz,N50:
359.1742.
Observed m/e: 359.1705. Analysis calculated for Cz,H~,NsO ~ HzO: C, 68.46; H, 6.02;
N, 19.01. Found: C, 68.38; H, 5.47; N, 18.66.
Examcle 34 1-(4-Methyl-1-piperazinyl)-7-(3-(3.3-dimethylformamidino)-2-pyridylaminol-naphthalene To a solution of the title product of example 29 (0.453, 1.36 mmol) in dry dimethyl formamide (5 mL) was added dimethyl formamide dimethyl acetal (5 mL, 35.4 mmol). The resulting solution was refluxed 4 hours and allowed to stir at room temperature overnight. The solvent was removed in vacuo and the residue was flash chromatographed on silica gel (1 x 7 inches). Gradient elution with from 50 to of ethyl acetate / hexane then a gradient of from 1 to 696 ethanol/ethyl acetate gave 0.352 g (67 96) of the title product as a yellow foam which was suitable for further reaction. A sample was recrystallized from ether gave the bright yellow crystalline title product for analysis: mp 108-111 °C. ' H NMR d 9.00 (d, J = 2 Hz, 1 H), 8.03-7.97 (m, 2H), 7.73 (d, J = 9 Hz, 1 H), 7.53-7.42 (sym m, 2H), 7.23 (t, J = 8 Hz, 1 H), 7.05-6.98 (sym m, 2H), 6.69 (dd, J = 5, 7.5 Hz, 1 H), 3.24 (br s, 4H), 3.13 (br s, 6H), 2.80 (br s, 4H), 2.46 (s, 3H). Analysis calculated for C23HzsNe: C, 71.10; H, 7.26; N, 21.63.
Found: C, 71.16; H, 7.17; N, 21.59.
Example 35 7-(Imidazolo(4,5-blpyridin-1-yl)-1-(4-methyl-1 p~erazinyl?-naphthalene The title product of example 34 (0.25 g, 0.64 mmol) was slurried in toluene and a catalytic amount of para toluenesulfonic acid (a couple of crystals) was added. The SUBSTITUTE SHEET (RULE 26) ~1-mixture was refluxed 4 hours, cooled and concentrated. The residue was taken up in methylene chloride and washed with saturated sodium bicarbonate and brine;
then it was dried over calcium sulfate and concentrated to a yellow oil (0.165 g). The oil was further purified by recrystallization from ether to afford 0.057 g (26 96) of the title product as yellow crystals: mp 107-112 ° C; ' H NMR a 8.65 (d, J = 2 Hz, 1 H), 8.52-8.48 (m, 2H), 8.21 (dd, _J = 1.5, 8 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.87 (dd, J = 2, 8 Hz, 1 H), 7.64 (d, -J = 8 Hz, 1 H), 7.46 (t, J = 8 Hz, 1 ), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.20 (d, J = 7 Hz, 1 H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H). Analysis calculated for C~,Hz,NS~HzO:
C, 71.57; H, 6.29; N, 19.87. Found: C, 71.32; H, 6.32; N, 19.44.
Example 36 7-(Imidazolof4 5-blpyridin-1-yl)-1-(4-meth~rl-1-piperazinyll-naphthalene The title product of example 29 (0.217 g, 0.65 mmol) was dissolved in acetic acid (3 mL) and diethyl ethoxymethylenemalonate (0.138 mL, 0.68 mmol) was added.
The mixture was stirred at 55°C for 5 hours. The reaction was cooled and diethyl ethoxymethylenemalonate (0.04 mL, 0.2 mmol) was added. The reaction was heated to 100°C overnight. The solvent was removed in vacuo and the residue was taken up in chloroform and neutralized with ice cold saturated sodium bicarbonate and washed with brine. The organic layer was dried over calcium sulfate, concentrated and flash chromatographed on silica gel (1 x 2.5 inches). Elution with methylene chloride and then 296 methanol/0.0596 ammonium hydroxide/methylene chloride gave an unweighed forerun. Continued elution with 496 methanol/0.0596 ammonium hydroxide/methylene chloride gave a tan oil which crystallized upon scratching. The crystals were collected, rinsed with ether, and dried to afford 0.066 g, (3096) of the title compound:
mp 107-112°C; 'H NMR a 8.65 (d, J = 2 Hz, 1H), 8.52-8.48 (m, 2H), 8.21 (dd, J
= 1.5, 8 Hz, 1 H), _8.04 (d, J = 8.5 Hz, 1 H), 7.87 (dd, J = 2, 8 Hz, 1 H), 7.64 (d, J = 8 Hz, 1 H), 7.46 (t, J = 8 Hz, 1 ), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.20 (d, J = 7 Hz, 1 H), 3.24 (br s, 4H), 2.75 (br s, 4H), 2.43 (s, 3H).
Example 37 7-(Benzimidazol-1-yl)-1-(4-methyl-1-piperazinyl)-naphthalene To a slurry of 10 96 palladium on carbon (0.022 g) in ethanol (5 mL) was added the product of example 28 (0.091 g, 0.25 mmol in 25 mL of dioxane). Methanol (5 mL) was added and the mixture was hydrogenated at 50 psi for 6 hours. The reaction was SUBSTITUTE SHEET (RULE 26) 2'58457 filtered through Celite and concentrated to afford n residue which was used without purification.
The above residue was dissolved in acetic acid (1.5 mL) and diethyl ethoxymethylenemalonate (0.058 mL, 0.29 mmol) was added. The mixture was stirred at 95°C for 2 hours. The mixture was chilled to 0°C and neutralized with 1 N NaOH.
The mixture was extracted with methylene chloride and this organic layer was washed with brine, dried through phase separating paper, end concentrated for flash chromatography on silica gel (1 x 2 inches). 50 to 10096 ethyl acetate/hexene gradient elution was not productive. Continued elution with 1 and 296 ethanol/ethyl acetate gave an unweighed forerun. Further elution with a gradient of trorn 4 to 1596 ethanol/ethyl acetate gave 0.083 g of a brown oil. The oil was recrystallized from ether to yield 0.039 g (4796) of the title compound as tan crystals: mp 148-150°C. 'H NMR 6 8.35 (d, J =
2 Hz, 1 H), 8.25 (s, 1 H), 8.04 (d, J_ = 8.5 Hz, 1 H), 7.94 (sym m, 1 H), 7.69-7.60 (m, 3H), 7.52 (t, J = 8 Hz, 1 H), 7.38 (sym m, 2H), 7.24 (d, J = 7.5 Hz, 1 H), 3.19 (br s, 4H), 2.70 (br s, 4H), 2.40 (s, 3H). HRMS m/e calculated for C~iH~~N,: 342.1840. Observed m/e:
342.1863.
Example 38 7-(3-Hydroxy-3-meth~t-1-butynyl~-1-(4-methyl-1-Qiperazinyl)-naphthalene crtoluene sulfonate 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.285 g, 0.761 mmol), 3-hydroxy-3-methylbutyne (0.12 ml, 1.24 mmol), triethylamine (0.52 mL, 3.73 mmol), and bis (iriphenylphosphine) palladium chloride (0.03 g, 0.04 mmol) were combined in dry dimethyl formamide (3 mL) and heated to 70 to 80°C.
After 40 min the reaction was cooled and poured into 30 mL of 1 N aqueous lithium chloride and extracted with ether (3 x 15 mL). The combined ether layer was washed wish water and brine; then it was dried over magnesium sulfate and concentrated to an orange oil. The oil was purified by flash chromatography on silica gel (1 x 6 inches). Elution with a gradient of ethyl acetate and hexane followed by 100' ethyl acetate gave 0.15 g of orange oily product (6596). The oil was dissolved in ether (5 mL) and p-toluene sulfonic acid (0.093 g, 0.489 mmol in ether) was added. An orange solid formed which was collected, rinsed well with ether and ethyl acetate. Recrystallization from ethanol/ether gave 0.113 g (3096) of the title product as a dark orange solid; mp 194.5-195.5°C. "C
NMF~ (DMSO d6) a 147.46, 145.70, 137.86, 133.54, 128.99, 128.66, 128.17, 127.75, *Trade-mark WO 94/21619 ~ PCT/US94/01206 ,-126.90, 125.59, 125.53, 124.23, 120.07, 116.59, 96.66, 81.06, 63.78, 53.02, 42.33, 31.70, 20.80.
Example 39 7-(2-Ethylsulfonyl)ethenyl-1-(4-methyl-l~ipera2iny11-naphthalene (L) tartrate The title product was prepared following the procedure of example 1 from 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 2-ethylsulfonyl-1-chloroethane (0.11 g, 0.7 mmol), triethylamine (0.47 mL, 3.37 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in dimethyl formamide (10 mL), the reaction being carried out at reflux for 4 hours followed by stirring at ambient temperature overnight. The product was purified by flash chromatography on silica gel (1 x 4 inches). Elution with 50 and 7596 ethyl acetate/hexane gave recovered starting material (0.07 g, 2896). Continued elution with ethyl acetate and then 1096 methanol/ethyl acetate gave 0.06 g (2696) of product; 'H
NMR a 8.31 (d, J = 1 Hz, 1 H), 7.85-7.77 (m, 2H), 7.62-7.44 (m, 3H), 7.15 (dd, J = 1.3, 7.2 Hz. 1 H), 6.90 (d, J = 15.5 Hz, 1 H), 3.19-3.10 (m, 6H), 2.75 (m, 4H), 2.45 (s, 3H), 1.42 (t, J = 7.5 Hz, 3H). The (L) tartrate salt was formed in methanol with 1 equivalent of (L) tartaric acid. Concentration of the methanolic solution and recrystallization from ethyl acetate/ether gave 0.035 g of light yellow hygroscopic solid title product: mp 110 120°C. Analysis calculated for C,9H~,NzOzS~C,HaOe~2Hz0: C, 52.07; H, 6.46; 0, 5.27.
Found: C, 51.70; H, 5.89; N, 5.11.
Example 40 7-(4-Chlorobenzylo~)-1-(4-meth-1-piperazinyl)-naphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol), 4-chlorobenzyl bromide (1.27 g, 6.18 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) ~ and refluxed 4.5 hours. The mixture was cooled to room temperature, filtered and concentrated to a yellow solid. This material was recrystallized from ether to yield 1.28 g (720) of 7-(4-chlorobenzyloxy)-a-tetralone as a light yellow solid: mp 91-92°C.
Analysis calculated for C"H,5CIOz: C, 71.20; H, 5.27. Found: C, 71.22; H, 5.20.
The product of the above reaction (1.0 g, 3.49 mmol) was combined with N
methylpiperazine (1.25 mL, 11.27 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.52 mL, 4.74 mmol) in methylene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to ambient temperature and stirred 2.5 hours; then it was SUBSTITUTE SHEET (RULE 26) 2~58~57 quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The THF
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 1.22 g (9596) of 7-(4-chlorobenzyloxy)-t-(4-rnethyi-1-piperazinyl)~,4-dihydronaphthalene as a light yellow solid: mp 115-116.5°C. Analysis calculated for C~~H=,CIN~O: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.54; H, 6.56; N, 6.95.
The product of the above reaction (1.2 g) was combined wish 1096 palladium on carbon (0.62 g, predried) in dry toluene (50 ml_) and refluxed. After several hours of retlux, 0.5 g more catalyst was added and the reaction was furlher refluxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded an orange oil which was purified by flash chromatography on silica gel (1 x 4 inches). Elution with 50 96 ethyl acetate/hexane gave unweighed recovered starting material. Continued elution as above gave 0.54 g of 7-hydroxy-1-(4-methyl-1-piperazinyi)-naphthalene. Furlher elution with ethyl acetate gave the title product (0.06 g). The title product was recrystallized from ether to afford 0.033 g (2.796) of light yellow solid: mp 111.5-112°C. Analysis calculated for C~1H?~CIN~O: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.92; H, 6.27; N, 7.69.
Example 41 7-(3-Methytaminosulfonylphenyl)-1-~(4-methyt-1 pi~erazinyf)naphthalene 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-rnett~ylaminosulfonyl-1-bromobenzene (0.18 g, 0.72 mmol), triethylarnine (0.45 rnL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) were combined in DMF (12.5 mL) and heated to 110 to 110°C for 45 minutes. The reaction was cooled to room temperature and 1 N aqueous lithium chloride (20 mL) was added. The mixture was extracted with ether (2x). The combined organic layer was washed with 1 N lithium chloride and brine; Then it was dried over magnesium sulfate and concentrated to an orange oil. Flash chromatography on silica gel (1 x 6 inches) with an ethyl acetate/hexane gradient of from 50 to 75'j6 followed by continued elution with ethyl acetate and finally rnethanol/ethyl acetate 0.11 g (4296) of the title product. The sample was recrystallized *Trade-mark WO 94/21619 ~~ ~ PCT/US94/01206 from ethyl acetate for analysis: mp 147.5-148°C. Analysis calculated for Cz=HnN~O~S:
C, 66.81; H, 6.31; N, 10.62. Found: C, 66.32; H, 6.16; N, 10.41.
Example 42 7-(3-Methylsutfonylaminophenyl)-1-(4-meth5rl-1-piperazinyl)-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylsulfonylamino-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours. The product was obtained in 3596 yield. A sample was obtained by recrystallization from ethyl acetate for analysis: mp 100-101 °C. Analysis calculated for CzzHz5N30~S~1.5 HBO: C, 62.54; H, 6.68; N, 9.94. Found: C, 62.70; H, 6.46; N, 9.89.
Example 43 7-Benzoyl-1-(4-methyl-1-piperazinyl)naphthalene 7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.1 g, 0.27 mmol), benzoyl chloride (0.031 mL, 0.27 mmol) and bis (acetonitrile) palladium chloride (0.007 g, 0.027 mmol) were combined in chloroform (5 mL) and heated to 60 to 65°C for 15 minutes. The reaction was cooled to room temperature and saturated aqueous ammonium chloride (10 mL) and chloroform (10 mL) were added. Phases were separated and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to a milky oil. The oil was purified by flash chromatography on silica gel (1 x 6 inches), the product eluting with 596 methanol/ethyl acetate as a yellow oil (0.07 g, 7996). The oil was crystallized from ether to obtain a bright yellow solid: mp 124-124.5°C. Analysis calculated for CzzH~zN~O: C, 79.97; H, 6.71; N, 8.48. Found:
C, 79.74; H, 6.69; N, 8.46.
Example 44 7-(a-Hydroxybenzyl)-1-(4-methyl-1-piperazinyl)-naphthalene The title product of example 43 (0.121 g, 0.366 mmol) was dissolved in ethanol (3 mL) and sodium borohydride (0.025 g, 0.66 mmol) was added. The mixture was stirred 1 hour at ambient temperature, then it was concentrated at reduced pressure at 40°C. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated to a light yellow oil. The oil was purified by SUBSTITUTE SHEET (RULE 26) flash chromatography on silica gel (1 x 4 inches). Elution with 5096 ethyl acetatelhexane removed a fast moving component which was not identfied.
Continued elution with ethyl acetate gave 0.066 mg of the title product as a light tan oil which solidified. This solid was recrystallized from chloroform/ether to afford 0.033 mg (2796) of the title product as a light tan solid: mp 162.5-163°C. Analysis calculated for C~zHz,N~O~0.25 HzO: C, 78.42; H, 7.33; N, 8.31. Found: C, 78.52; H, 7.06; N, 8.31.
Example 45 7-(Diahenylhydroxymethyll-1-(4-methyl-1-aiaerazinvl)-naphthalene The title product of example 43 (0.072 g, 0.218 mmol) was dissolved in dry THF
(10 mL) and chilled to 0°C. Phenyl magnesium bromide (3 M in ether, 0.08 mL, 0.24 mmol) was added dropwise. The mixture fumed greenish and then returned to a yellow color. The reaction was allowed to warm to room temperature for 30 minutes and then refluxed for 45 minutes. Additional phenyl magnesium bromide (0.1 mL, 0.26 mmol) was added and the mixture was refluxed 1 hour more. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to a light yellow oil. The product was purified by silica gel flash chromatography (1 x 6 inches).
Elution with 5096 ethyl acetate/hexane followed by ethyl acetate gave 0.082 g (9296) of the title product. A sample was recrystallized from chloroform/ether for analysis: mp 217.5-218.5°C. Analysis calculated for CzeH~eN~O~0.5 HBO: C, 80.54; H, 7.00; N, 6.71.
Found: C, 80.47; H, 6.63; N, 6.78.
Example 46 7-(p-Biphenyll-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 4-bromobiphenyl (0.17 g, 0.73 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1 hour at 100 to 115°C.
The product obtained was 0.14 g (56°k) in yield. A sample was obtained by recrystallization from ether/hexane for analysis: mp 138.5-139.5°C. Analysis calculated for C~,H~NZ: C, 85.67; H, 6.92; N, 7.40. Found: C, 85.12; H, 6.97; N, 7.44.
SUBSTITUTE SHEET (RULE 26) ~47-Example 47 7-(3-Methoxycarbonylphenyl)-1-(4-methyl-1 piperazinyl)-naphthalene The title product was prepared following the procedure of example 41 from 7 trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3 methoxycarbonyl-1-bromobenzene (0.16 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours at 120 to 130°C. The product obtained was 0.15 g (6396) in yield as an oil which was converted to a hydrochloride salt with HCI gas in ether. The solid was collected under a nitrogen atmosphere and recrystallized from chloroform/ether for analysis:
mp 201-203°C; "C NMR d 167.05, 147.37, 141.78, 137.80, 134.08, 131.87, 130.89, 129.57, 129.07, 128.63, 128.47, 126.28, 125.76, 125.02, 120.59, 116.85, 54.30, 52.33, 49.75, 43.70.
Example 48 7-l3-Fluorophenvl)-1-(4-methyl-1-piperazinyll-naphthalene The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-fluoro-1-bromobenzene (0.13 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 2 hours at 120 to 130°C.
The product obtained was 0.13 g (5996) in yield. A sample was obtained by recrystallization from ether/hexane for analysis: mp 116-116.5°C. Analysis calculated for C2zH~,FNz: C, 79.49; H, 6.37; N, 8.43. Found: C, 79.07; H, 6.46; N, 8.66.
Example 49 7-(BenzyIoxY)-1-(4-meth~rl-1-piperazinyl)-naphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol), benzyl bromide (0.80 mL. 6.73 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed 22 hours. The mixture was cooled to room temperature, filtered and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The phases were separated and the organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated to a pale yellow solid. The material was recrystallized from ether/hexane SUBSTITUTE SHEET (RULE 26) to yield 0.80 g (51%) of 7-benzyloxy-v-tetrnlone as a cream solid: mp 84-84.5°C.
Analysis calculated for C"ti,a0i: C, 80.93; H, 6.39. Found: C, 80.39; H, 6.11.
The product of the above reaction (0.75 g, 2.97 mmol) was combined with N
methylpiperazine (1.06 mL, 9.56 mmol) (n dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.44 mL, 4.01 mmol) in methyiene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to ambient temperature end stirred overnight; then it was quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The TI-F
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2 x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 0.93 g (9496) of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene as an orange oil which was suitable for use without further purification. 'H NMR d 7.48-7.28 (m, 5H), 7.08-7.05 (m, 2H), 6.79 (dd, J =
2.7, 8.2 Hz, 1 H), 5.30 (t, ~ = 4.7 Hz), 5.10 (s, 2H), 2.84 (br s, 4H), 2.64-2.50 (t, J_ =
7.5 t-iz t 5 overlapping wish br s centered at 6 2.54, 6H total), 2.37 (s, 3H), 2.25-2.17 (m, 2H).
The product of the above reaction (0.93 g, 2.78 mmol) was combined with 1096 palladium on carbon (0.65 g, predried) in dry toluene (30 mL) and reRuxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded a yellow oil which was purified by (lash chromatography on silica gel (1 x 4 inches). Elution with 5096 ethyl acetate/hexane gave unweighed recovered starting material. Continued elution with 7596 ethyl acetate/hexane gave 0.18 g of 7-benzyloxy-1-(4-methyl-1-piperazinyl)-naptothalene es a colorless oil. Recrystallization from ether gave 0.09 g (9.896) of the tile product as a white solid: mp 81.5-82.5°C. Analysis calculated for C7,li"N,O: C, 79.48; t-1, 7.28; N, 8.43. Found: C, 79.29; H, 7.41; N, 8.30. Further elution with ethyl acetate gave 0.47 g of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene.
Example 50 7-(3,4-Dichlorobenzyloxy~i-1-(4-methyl-1_piperazinyll-naphthalene 7-Hydroxy-o-tetralone (1.0 g, 6.17 mmol), 3,4-dichlorobenzyl bromide (t .48, G.18 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were combined in acetone (50 mL) and refluxed 21.5 hours. The mixture was cooled to room temperature, filtered and concentrated at reduced pressure. The reside was partitioned between ethyl acetate and 1 N sodium hydroxide. The phases were separated and the organic layer was *Trade-mark washed with water and brine; then it was dried over magnesium sulfate and concentrated to a pale yellow solid. This material was recrystallized from ether to yield t .04 g (5396) of 7-(3,4-dichlorobenzyfoxy-a-tetralone as a fluffy white solid: mp 122.6-123°C. Analysis calculated for C"H"CItO~: C, 63.57; ti, 4.39. Found: C, 63.36; H, 4.21.
The product of the above reaction (0.90 g, 2.8 mmol) was combined with N-methylpiperazine (1.0 mL, 9.01 mmol) in dry tetrahydrofuran (THF, 50 mL) and chilled to -78°C. A solution of titanium tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL) was added dropwise over 3 minutes resulting in a milky green solution.
The reaction was warmed to arnbient temperature and stirred overnight; then it was quenched with 50 mL of a 2/1 mixture of water and ammonium hydroxide. The THF
was removed with a stream of nitrogen. The residual aqueous phase was extracted with ethyl acetate (2x). The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 1.08 g (9696) of 7-(3,4-dichlorobenzyloxy-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene as a yellow oil which was suitable for use without further purification. ' H NMR ~ 7.55 (d, J=2 Hz, 1 H), 7.45 (d, J=8.2 Hz, 1 H), 7.29-7.25 (m, _1 H), 7.07 (d, J=8.2 Hz, 1 H), 7.00 (d, J=2.7 Hz, 1 H), 6.75 (dd, J=2.7, 8.2 Hz, 1 H), 5.30 (t, J=4.7 Hz, 1 H), 5.05 (s, 2H), 2.80 (br s, 4H), 2.63-2.43 (m, 6H), 2.36 (s, 3H), 2.30-2.16 (m, 2H).
The product of the above reaction (1.08 g, 2.68 mmol) was combined with 1096 palladium on carbon (0.65 g, predried) in dry toluene (30 mL) and refiuxed overnight.
The reaction was cooled to room temperature and filtered throughCelite. The pad was rinsed well with ethyl acetate. Concentration yielded a brown oil which was purified by (lash chromatography on silica gel (1 x 4 inches). Elution with 7596 elhyi acetate/hexane gave an unweighted forerun. Continued elution with ethyl acetate gave 0.22 g of light yellow solid. Recrystallization from ether gave 0.148 g (1496) of the title product as a straw colored solid: mp 113-114°C. Analysis calculated for C"H?iCI,N~
O: C, 65.84; H, 5.53; N, 6.98. Found: C, 66.18; H, 5.63; N, 7.02.
Example 51 7-(4-Tritluoromethylbenzyloxy~-~4-methyl-1-piperazinyll-naphthalene To a mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.20 g, 0.83 mmol), triphenylphosphine (0.32'g, 1.22 mmol), and 4-tritluoromethylbenzyl alcohol (0.17 mL, 1.26 mmol) in dry THF (4 mL) was added diethyl azodicarboxylate in Tt-iF (1 *Trade-mark mL). The mixture was stirred ovemlght at ambient temperature; then it was concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic layer was washed with water and brine;
then it was dried over magnesium sulfate and concentrated onto silica gel for flash chromatographic purification (1 x 6 inches). Elution with 7596 ethyl acetate/hexane gave 0.24 g (7296) of the title compound as a nearly colorless oil. The oil was treated with HCI in ether to form the hydrochloride salt (0.23 g) which was recrystallized from chloroform/ether to give 0.14 g of a white solid thereof: mp 205-206°C.
Analysis calculated for C~~Hz~F~N~O~HCI~0.25 HzO: C, 62.58; H,. 5.59; N, 6.35. Found:
C, 62.59; H, 5.63; N, 6.40.
Example 52 7-Benzoylo~-1-(4-methyl-1-pJ~erazinyl~-naphthalene A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a second equivalent of benzoyl chloride was added with continued stirring overnight. The reaction was diluted with ethyl acetate and the phases were separated.
The organic layer was washed with 1 N sodium hydroxide, water and brine; then it was dried over magnesium sulfate and concentrated to an oil which solidified (0.065 g, 6996). A sample recrystallized from ether/hexane as a light pink solid was submitted for analysis: mp 82-82.5°C. Analysis calculated for C~=H==NzO~~0.25 HBO: C, 75.30;
H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Example 53 7-(4-Chlorobenzovloxy,)-1-(4-methyl-1-piperazinyl l-naphthalene The title product was obtained following the procedure of example 30 from 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and 4-chlorobenzoyi chloride (0.035 mL, 0.275 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) with a second equivalent of 4-chlorobenzoyl chloride added after several hours of stirring at room temperature. The title product was obtained in a yield of 0.058 g (5796) after recrystallization from ether/hexane: mp 110-111 °C. Analysis calculated for CzzHz,CIN~O~: C, 69.38; H, 5.56; N, 7.36. Found:
C, 69.31; H, 5.61; N, 7.35.
SUBSTITUTE SHEET (RULE 26) ~~1'S8 ~~'~
Example 54 7-(3-Chlorobenzyloxvl-1-(4-methyl-1-picen3zinvl)-naphthalene A mixture of 3-chlorobenzyi bromide (1.27 g, 6.18 mmol), 7-hydroxy-a-tetralone (1.0 g, 6.17 mmol), and potassium carbonate (1.7 g, 12.3 mmol) in acetone (30 mL) was refluxed overnight. The reaction was cooled, flttered, and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1 N sodium hydroxide. The organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to a yellow solid. Reaystallization from ether/hexane gave 0.87 g (4996) of 7-(3-chlorobenzyloxy)-a-tetralone as a cream colored solid: mp 77-78°C. Analysis calculated for C"H,5CI0=: C, 71.20; H, 5.27. Found:
C, 71.25; H, 5.09.
A solution of 7-(3-chlorobenzyloxy)-a-tetralone (0.8 g, 2.79 mmol) and 1-methylpiperazine (1.0 mL, 4.0 mmol) in dry THF (50 mL) was cooled to -78°C and treated with titanium tetrachloride (0.42 mL, 3.83 mmol) in methylene chloride (2 mL).
The reaction was stirred 10 minutes at -78°C, then warmed to room temperature and stirred overnight. The mixture was quenched with 50 mL of 5 N ammonia and extracted with ethyl acetate (2x). This combined organic layer was dried over magnesium sulfate and concentrated to a colorless oil (0.98 g, 9596). This enamine was used directly in the next step.
A mixture of the enamine (1.0 g, 2.71 mmol) and sulfur (1.1 g, 34.31 mmol) in decalin (10 mL) was lowered into an oil bath preheated to 170°C. The mixture was stirred 20 minutes; then it was cooled and the decalin was removed by short path distillation. The residue was dissolved in carbon disulfide and flash chromatographed on silica gel (1 x 6 inches). Elution with carbon disulfide removed residual sulfur.
Continued elution with 5096 ethyl acetate/hexane and finally with pure ethyl acetate gave 0.09 g of brown oil. The product was combined with 0.03 g of product from a previous preparation and treated with decolorizing carbon in ether. Recrystallization from hexane gave 0.026 g (2.696) of the title product as a light yellow solid: mp 67.5-68°C.
Analysis calculated for Cz~Hz,CIN20: C, 72.02; H, 6.32; N, 7.64. Found: C, 71.95; H, 6.32; N, 7.47.
SUBSTITUTE SHEET (RULE 26) temple b5 7-Tritluorometh~,risulfonyloxY-1-(4-methyf-1-eiperaziny~l ~-naphthalene 7-Hydroxy-1-(4-methyl-1-piperazlnyl)-naphthalene (4.1 g, 16.9 mmol) and triethylarnine (12.8 mL, 91.8 mmol) were dissolved in methytene chloride (150 mL) and cooled to -78°C. Triflic anhydride (3.04 mh 18.1 mmol) was added via syringe and tl~e reaction was warmed to room temperature and stirred overnight. The reaction was again chilled to -78°C and additional triflic anhydride (1 ml-) and triethyfamine (2 mL) were added but after 2 hours stirring nt ambient temperature, no further reaction occurred. Saturated ammonium chloride was added and the mixture was concentrated.
The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to a brown oil which was purified by silica gel flash chromatography (2 x 6 inches). Elution with 7596 ethyl acetate/hexane gave 4.49 g (7196) of the title product as a light brown solid: mp 7U-71 °C. Analysis calculated for C,aH"F~NIO,S: C, 51.33; H, 4.58; N, 7.48.
Found: C, 51.35; H, 4.46; N, 7.49.
Example 56 7-8enzamido-1-(4-methyl-1-piperezinvll-naphthalene 7-Benzamido-1-(4-methyl-1-piperazinyl)-3,4-dihydronaphthalene (0.795 g, 2.29 rnmol, an intermediate from Exarnple 1), freshly distilled dicyclopentadiene (70°C at 1 Torr, 0.909 g, 6.87 mmol), and 1096 palladium on carbon (0.2 g, predried) were combined in xylene (25 mt_)~ and retluxed 4 hours. The mixture was cooled and additional palladium on carbon (0.3 g) was added. The reaction was refluxed vigorously and xyfene was distilled out of the reaction until the volume of the reaction was reduced to about 10 mL. The reaction was retluxed overnight, cooled, and filtered *
throughCelite. The filtrate was concentrated on silica gel and flash chromatographed on silica gel. Gradient elution with from 5096 to 10096 ethyl acetate/hexane gave a forerun containing an unweighed amount of 7-benzamido-o-tetralone. Continued gradient elution with 29'° to 1096 methanol/ethyl acetate gave 0.49 g (6296) of the title product: mp 172-173.5°C.
Alternatively, (2,2,2) bicyclooctene was used in place of dicyclopentadiene in the above dehydrogenation reaction to produce the title product in 6696 yield after recrystallization horn ethyl acetate/hexane.
*Trade-mark ~~,1'~
Example 57 7-Amino-1-(1-methvl~-piperidinvll-naphthalene The following reaction was run in two side by side reactions and the crude products were combined for work up and purification. A mechanically stirred solution of 8-bromo-2-(dibenzylamino)-naphthalene (10.0 g, 24.9 mmol from Preparation 4) in tetrahydrofuran (200 mL) was cooled to -95°C (hexane/liquid nitrogen) and butyllithium (10.39 mL, 24.9 mmol, 2.4 M) was added dropwise. The orange solution was stirred 7 min, then 1-methyl-4-piperidone (2.82 g, 24.9 mmol) was added dropwise over minutes with a 10 mL tetrahydrofuran rinse. The orange color faded while stirring was continued 20 minutes at -100°C. The reaction was allowed to warm to room temperature and quenched with water. The solvent was removed and the residue was partitioned between methylene chloride and water (at this point the two reactions were combined). The phases were separated and the organic layer was washed with brine, dried, and concentrated onto silica gel. Flash chromatography (4 x 4 inches silica gel) proceeded as follows: methylene chloride (1 L) and 296 methanol / methylene chloride (1.6 L) unweighed white solid 7-dibenzylaminonaphthalene; 1596 methanol /
methylene chloride (1 L), 2596 methanol / methylene chloride (1 L) and 3096 methanol /
methylene chloride / 0.296 ammonium hydroxide (4 L) product contaminated with water. The combined eluents were concentrated and redissolved in methylene chloride. The solution was dried and concentrated to afford 15.09 g (6996) of 7-dibenzylamino-1-(4-hydroxy-1-methyl-4-piperidinyl)-naphthalene as a light tan foam. A sample recrystallized from ethyl acetate had mp 173-174°C. Analysis calculated for C3°H3~N~0: C, 82.53;
H, 7.39; N, 6.42. Found: C, 82.42; H, 7.44; N, 6.38.
The product from the above reaction (15.0 g, 34.38 mmol), p-loluenesulfonic acid (7.85 g, 41.26 mmol) and toluene (500 mL) were combined and refluxed 4 hours with azeotropic removal of water. The mixture was allowed to stand at room temperature 48 hours, then additional p-toluenesulfonic acid (1.4 g) was added and the mixture was refluxed 5 hours more. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. This organic phase was washed with 1 N sodium hydroxide (2 x) and brine, then it was dried over calcium sulfate and concentrated to give 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphthalene as a brown oil which crystallized on standing (13.8 g, 9696).
This material was suitable for use in the next reaction. A sample recrystallized from ethyl SUBSTITUTE SHEET (RULE 26) ry W0 94/21619 PCT/US94/01206 acetate had mp 124-126°C. The analytical sample was recrystallized from isopropanol.
Analysis calculated for C,°H,°N~ ~ 0.5 HsO: C, 84.27; H, 7.31;
N, 6.69. Found: C, 83.85; H, 6.97; N, 6.39.
A mixture of 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-naphtha lene (2.85 g, 6.81 mmol) and palladium hydroxide (2096 on carbon, 2.06 g) in glacial acetic acid (60 mL) was hydrogenated 22 hours (starting pressure approximately psi). Additional palladium hydroxide (1 g) was added and hydrogenation was continued 13 hours more. The reaction was filtered through celite. The filtrate was neutralized with 4 N sodium hydroxide and extracted with methylene chloride.
This organic phase was washed with brine, dried and concentrated to 1.3 g of brown oil.
Crystallization from isopropanol gave 0.544 g (3396) of 7-amino-1-(1-methyl-4-piperidinyl)-naphthalene as light brown crystals. mp 169.5-171 ° C.
Analysis calculated for C,eH~°N~: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.14; H, 8.42; N, 11.52.
Example 58 7-(3-vitro-2-pyridvlamino,~-1-(1-methyl-4-piperidinyl)-naphthalene A mixture of the product from Example 57 (0.338 g, 1.4 mmol), 2-chloro-3-nitropyridine (0.446 g, 2.81 mmol), and 4-dimethylami~opyridine (0.172 g, 1.4 mmol) in dimethylformamide (6 mL) was refluxed 5 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1 N sodium hydroxide and brine, then it was concentrated onto silica gel and flash chromatographed (1 x 4 inches silica gel). The elution proceeded as follows: 7596 methylene chloride / hexane (175 mL) nil; methylene chloride (250 mL) unweighed excess 2-chloro-3-nitropyridine; 296 methanol / methylene chloride (200 mL) nil, (550 mL) 0.373 g of crude product contaminated with 4-dimethylamino-pyridine.
This material was triturated with ether and filtered to give 0.17 g of title product as orange crystals. 'H NMR d 10.34 (br s, 1 H), 8.59 (dd, J = 2, 8.5 Hz, 1 H), 8.54-8.50 (m, 2 H), 7.88 (d, J = 9 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.45 7.41 (m, 2 H), 6.89 (dd, J = 4.5, 8.5 Hz, 1 H), 3.27 (tt, J = 4, 11.5 Hz, 1 H), 3.11 (long range coupled d, J = 11.5 Hz, 1 H), 2.41 (s, 3 H), 2.27 (dt, J = 2.5, 11.5 Hz, 2 H), 2.09 1.89 (m, 4 H).
SUBSTIT1JTE SHEET (RULE 26) WO 94/21619 ~~ PCT/US94/01206 Example 59 7-(Imidazolof4 5-b)pyridin-1-yl)-1-(1-methyl-4-piperidinvl)-naphthalene A mixture of the product from Example 58 (0.18 g, 0.5 mmol) and 10% palladium on carbon (0.04 g) in ethanol (35 mL) and ethyl acetate (15 mL) was hydrogenated at 45 psi for 4 hours. The mixture was filtered through celite and concentrated to give 7-(3-amino-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene which was suitable for further reaction; ' H NMR d 8.07 (d, J = 2 Hz, 1 H), 7.89 (dd, J = 1.5, 5 Hz, 1 H), 7.79 (d, J = 9 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45 (dd, J = 2, 9 Hz, 1 H), 7.36-7.26 (m, 2 H with CHCh from NMR solvent overlapping), 7.07 (dd, J = 1.5, 7.5 Hz, 1 H), 6.82 (dd, J = 5, 7.5 Hz, 1 H), 6.51 (br s, 1 H), 3.49 (br s, 2 H), 3.18 (tt, J = 4, 12 Hz, 1 H), 3.03 (long range coupled d, J = 13.5 Hz, 2 H), 2.39 (s, 3 H), 2.23 (dt, J =
2.5, 11.5 Hz, 2 H), 2.08-1.87 (m, 4 H). HRMS m/e calculated for C~,H=,N,: 332.1996. Observed m/e 332.2003.
The product from the above reaction and ethoxymethylenemalononitrile (0.079 g, 0.646 mmol) were combined in glacial acetic acid (7 mL) were refluxed 4 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1 N sodium hydroxide and brine, then it was dried and concentrated. This residue was flash chromatographed on silica gel (1 x 3.5 inches). Gradient elution with from 5096 ethyl acetate / hexane to pure ethyl acetate and then with from 2% to 596 methanol / ethyl acetate gave no product.
Continued elution with from 15% to 4096 methanol / ethyl acetate gave a tan foam product. Treatment with charcoal in methylene chloride, filtration and concentration gave 0.155 g of product. Recrystallization from ethyl acetate gave 0.04 g (2396) of the title compound as off white crystals. mp 118-120°C. Analysis calculated for C~ZH?~N,:
C, 77.16; H, 6.48; N, 16.36. Found: C, 76.99, H, 6.45; N, 16.27.
Example 60 7-(4-Chlorobenzamido-1-(1-methyl-4-piperidinyl)-naphthalene The product from Example 57 (0.202 g, 0.845 mmol), triethylamine (0.124 mL, 0.93 mmol) and 4-chlorobenzoyl chloride (0.118 mL, 0.93 mmol) were combined in acetonitrile (10 mL) at 0°C. The mixture was allowed to come to room temperature and stir overnight. The reaction was chilled back to 0°C and a second equivalent of acid chloride and triethylamine were added. The mixture was heated to 90°C
overnight.
The solvent was removed at reduced pressure and the residue was taken up in SUBSTITUTE SHEET (RULE 2fi) methylene chloride. The organic phase was washed with brine, dried, concentrated onto silica gei and flash chromatographed (0.5 x 3.5 inches). Elution proceeded as follows: methylene chloride then gradient elution with from 2% to 4% methanol /
methylene chloride was unproductive. Continued elution with from 4% to 696 methanol / methylene chloride gave 0.214 g of white foam. Recrystallization from chloroform /
ether gave 0.115 g of the title compound as tan crystals. mp 162-164°C.
The compound was converted to its hydrochloride salt with HCI in ether. Analysis calculated for C"Hz,CINzO ~ HCI: C, 66.51; H, 5.82; N, 6.74. Found: C, 66.12;
H, 5.76; N, 6.41.
Example 61 7-Amino-1-(1-methyl-3-~iperidinvl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (9.75 g, 24.3 mmol product of Preparation 4) in tetrahydrofuran (270 mL) was cooled to -78°C and butyllithium (9.72 mL, 24.4 mmol, 2.4 M) was added dropwise. The orange solution was stirred 20 minutes, then 1-t-butoxycarbonyl-3-piperidone (4.84 g, 24.3 mmol dissolved in 5 mL
tetrahydrofuran ) was added dropwise with a 5 mL tetrahydrofuran rinse. The reaction was stirred 30 minutes at -78°C, then allowed to warm to room temperature and stir 1 hour. The solvent was removed and the residue was partitioned between methylene chloride and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate, and concentrated onto silica gel. Flash chromatography (3 x 3 inches silica gel) proceeded as follows: 5% ethyl acetate /
hexane (1.4 L) and 1096 ethyl acetate / hexane (1 L) unweighed white solid 7-dibenzylaminonaphthalene; 25%ethyl acetate / hexane (1.5 L) 6.46 g (51%) of 7-dibenzylamino-1-(1-t-butoxycarbonyl-3-hydroxy-3-piperidinyl)-na phthalene which was suitable for use without further purification. A sample recrystallized from ethyl acetate / hexane had mp 145-147°C.
The product of the above reaction (1.0 g, 1.9 mmol) and dry benzene (20 mL) were chilled to 0°C and Burgess salt (0.958 g, 4.02 mmol) was added.
The mixture was heated to 55°C for 2 hours, then allowed to stir at ambient temperature overnight.
Water was added and after stirring an additional 15 minutes, the phases were separated. The organic layer was washed with brine and the combined aqueous washes were back extracted with ethyl acetate. The combined organic layer was dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1 x 3 SUBSf ITUTE SHEET (RULE 26) inches). Elution 2% to 496 ethyl acetnta / hexane gave 0.68 g (70%) of a mixture of both possible dehydration products (7-dibenzylamino-1-(1-t-butoxycarbonyl-1,4,5,6-tetrahydropyrid~-yl)-naphthalene and 7-dibenzylamino-1-(1-t-butoxycarbonyi-1,2.5,6-tetrahydropyrid-3-yt)-naphthalene). The products could be separated by careful chromatography but were carried as a mixture in this sequence.
A slurry o1 lithium aluminunn hydride (0.172 g, 4.52 mmol) in tetrahydrofuran (20 mL) was chilled to 0°C and the product of the above reaction (0.568 g, 1.13 mmol in 5 mL tetrahydrofuran) was added with a tetrahydrofuran rinse (2 x 2.5 mL). The mixture was refluxed 4 hours, chilled to O°C and quenched with sodium sulfate decahydrate.
t O The reaction was filtered and the filter cake was rinsed well with methyfene chloride.
The filtrate was concentrated and the residue was taken up in methyfene chloride. This organic phase was washed with water and brine, dried and concentrated to give 0.455 g of a 2:1 mixture of oleTin products (7-dibenzylamino-1-(1-methyl-1,4,5,6-tetrahydro-pyrid-3-yl)-naphthalene and 7-dibenzylamino-1-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-naphthalene) as judged by integration of the methyl signals in the NMR
spectrum (2.52 ppm - major and 2.27 ppm - minor). This material was carried on without further purification or characterization.
The product mixture from the above reaction (4.0 g, 9.56 mmol) and palladium hydroxide (2096 on carbon, 3.75 g) in glacial acetic acid (141 mL) and ethanol (141 mL) was hydrogenated 4 hours (starting pressure approximately 50 psi). Additional palladium hydroxide (0.8 g) was added and hydrogenation was continued 5 hours more. The reaction was filtered through Celite. The filtrate was neutralized with 4 N
sodium hydroxide and extracted with methylene chloride. This organic phase was washed with brine, dried, concentrated onto silica gel and flash cloromatographed (2 x 3 inches). Elution proceeded as follows: 7596 ethyl acetate / hexane (400 mL), ethyl acetate (400 mL), and 296 methanol / ethyl acetate (400 mL), nil; 296 triethylamine / 596 methanol / ethyl acetate (400 mL), 0.45 g of an unidentified brown loam; 296 triethylamine / 6'j6 methanol / ethyl acetate (500 roL) and 396 triethylamine methanol / ethyl acetate (500 mL), 1.35 g (549'0) of brown foam title product.
Further purification by treatment with activated charcoal followed by trituration in ether gave 0.362 g of the title compound as pink crystals which had mp 117-120°C.
HRMS rn/e calculated for C,aH7°N~: 240.1622. Observed m/e 240.1623. Analysis calculated for C,eH,°N~: C, 79.96; H, 8.39; N, 11.66. Found: C, 80.02; H, 8.22; N, 11.10.
*Trade-mark 21584~'~
Example 62 7-(3-Nitro-2-nyridylamino)-1-( 1-methyl-oiperidinvl)-nachthalene A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from Example 61 ), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL, 1.05 mmol) in dimethylfortnamide (10 mL) was refluxed overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride.
The organic phase was washed with 0.5 N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 3 Inches). Elution proceeded as follows: 5096 ethyl acetate / hexane (500 mL) unweighed forrun;
ethyl acetate / hexane (400 mL) and ethyl acetate (100 mL) 0.151 g (5196) of red oil product. A sample crystallized from ether gave the title compound as red crystals. mp 107-108°C. Analysis calculated for C~,H~~N,Oz: C, 69.59; H, 6.12; N, 15.46. Found:
C, 69.30; H, 5.91; N, 14.92.
~.-xamole 63 7-~(Imidazolof4.5-blpyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene A mixture of the 7-(3-vitro-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene (0.12 g, 0.33 mmol from Example 62) and t 096 palladium on carbon (0.03 g) in ethanol (10 mL) and methanol (20 mL) was hydrogenated at 50 psi for 4 hours. The reaction was filtered through celite and concentrated to the brown oil product (7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene) which was suitable for use without further purification. ' H NMR a 7.89-7.83 (m, 2 H), 7.78 (d, J = 9 Hz, 1 H), 7.64 (dd, J
= 2, 9 Hz, 2 H), 7.33-7.23 (m, 2 H, partially obscurred by NMR solvent), 7.02 (dd, J =
1.5, 7.5 Hz, 1 H), 6.78 (dd, J = 5, 7.5 Hz, 1 H), 6.55 (br s, 1 H), 3.54 (long range coupled t, J = 11.5 Hz, 1 H), 3.18 (long range coupled dd, J = 1.5, 11 Hz, 1 H), 2.99 (long range coupled d, J = 10.5 Hz, 1 H), 2.34 (s, 3 H), 2.17-1.97 (m, 3 H), 1.94-1.81 (sym m, 2 H), 1.69-1.51 (m, 1 H). HRMS m/e calculated for CI,H~,N,: m/e 332.2000.
Observed m/e 332.2002.
A mixture of 7-(3-amino-2-pyridylamino)-1-(1-methyl-3-piperidinyl)-naphthalene (0.104 g, 0.313 mmol) and ethoxymethylenemalononitrile (0.056 g, 0.459 mmol) in glacial acetic acid (5 mL) was refluxed 6 hours. The reaction was cooled, neutralized with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows: 5096 ethyl SUBSTITUTE SHEET (RULE 26) acetate / hexane (200 mL), 7596 ethyl acetate / hexane (200 mL), ethyl acetate (200 mL) and 196 methanol / 196 triethylamine / ethyl acetate (300 mL) nil; 396 methanol / 396 triethylamine / ethyl acetate (300 mL) 0.076 g (70 96) of 7-(imidazolo[4,5-b]pyridin-1-yl)-1-(1-methyl-3-piperidinyl)-naphthalene as a faint green oil. The product was characterized as its HCI salt which crystallized from isopropanol. mp >
250° C. ' H
NMR (DSO) d 9.30 (br s, 1 H), 8.51 (d, J = 5 Hz, 1 H), 8.40 (s, 1 H), 8.32 (d, J = 7.5 Hz, 1 H), 8.11 (d, J = 9 Hz, 1 H), 7.94 (d, J = 8 Hz, 1 H), 7.73 (dd, J = 2, 9 Hz, 1 H), 7.68-7.53 (m, 3 H), 3.77 (long range coupled t, J = 11.5 Hz, 1 H), 3.62 (br t, J = 10.5 Hz, 2 H), 3.22 (t, J = 12.5 Hz, 1 H), 3.07 (sym m, 1 H), 2.87 (s, 3 H), 2.23-2.05 (m, 2 H), 2.04-1.78 (sym m, 2 H). Analysis calculated for CzZH~~N, ~ 2HCI ~ HBO: C, 60.97; H, 6.05; N, 12.93. Found: C, 60.89; H, 6.00; N, 12.61.
ExamJ~le 64 7-Benzamido-1-(1-methyl-3-piperidinyl)-naphthalene A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.203 g, 0.845 mmol, product of example 61 ) and triethylamine (0.141 mL, 1.01 mmol) in tetrahydrofuran (5 mL) was chilled to 0°C and benzoyl chloride (0.118 mL, 1.01 mmol) was added. The mixture was warmed to room temperature and stirred overnight.
The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was extracted with 0.5 N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2 inches).
Elution proceeded as follows: 5096 ethyl acetate / hexane (225 mL), 7596 ethyl acetate / hexane (150 mL) nil; 7596 ethyl acetate / hexane (400 mL) and ethyl acetate (200 mL) 0.198 g of pink foam. This product was converted to an HCI salt in methanol, treated with activated carbon, and filtered. The filtrate was concentrated and triturated with ether to give 0.091 g (3196) of the title compound as an amorphous solid with a melting range of 140-170°C. 'H NMR (DMSO da) a 10.59 (s, 1 H), 10.34 (br s, 1 H), 8.73 (s, 1 H), 8.06 (d, J = 7 Hz, 2 H), 7.94 (distorted t, J = 10 Hz, 2 H), 7.82 (d, J =
7 Hz, 1 H), 7.63-7.53 (m, 3 H), 7.47-7.39 (m, 2 H), 3.78 (br t, J = 12 Hz, 1 H), 3.56 (br t, J = 11 Hz, 2 H), 3.05 (br s, 1 H), 2.83 (br s, 3 H), 2.15-1.97 (m, 2 H), 1.71 (br s, 1 H). HRMS m/e calculated for Cz,H~4Nz0: m/e 344.1883. Observed m/e 344.1886.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 215 8 4 ~ ~ pCT~S94101206 Example 65 7 (4-Chlorobenzamido) 1-(4-methoxyethyl-1-pi~erazinvl)-naphthalene A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol, product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164 mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile (7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced pressure. The residue was taken up in methylene chloride and washed with 1 N sodium hydroxide and brine, dried, concentrated , onto silica gel and flash chromatographed (1 x 2.5 inches). Elution proceeded as follows: 5096 ethyl acetate / hexane (100 mL) and 7596 ethyl acetate / hexane (100 mL), nil; 7596 ethyl acetate /
hexane (100 mL) and ethyl acetate (150 mL), 0.121 g (6996) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene as an oil. This oil was converted to the HCI
salt from an ether solution. An amorphous white powder hydrochloride salt of the title compound was obtained. mp 134-148°C. 'H NMR a 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J = 9 Hz, 3 H), 7.66 (dd, J = 2, 9 Hz, 1 H), 7.55-7.43 (m, 3H),7.36(t,J=8Hz,1 H),7.11 (dd,J= 1,7.5 Hz, 1 H),3.57(t,J=5.5Hz,2H), 3.38 (s, 3 H), 3.19 (br s, 4 H), 2.83 (br s, 4 H), 2.70 (t, J = 5.5 Hz, 2 H).
Analysis calculated for C~,H~eCIN,O=~2HCI~l.5Hz0: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Example 66 7 (4 -Chlorobenzamido)-1-(4-propel-1-piperazinyl)-naphthalene A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol, the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride (0.103 g, 1.64 mmol) in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient temperature for 20 hours. The solvent was removed at reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Phases were separated and the organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1 x 3 inches). Elution proceeded as follows: ethyl acetate (50 mL) unweighed forrun;
ethyl acetate (250 mL) 0.164 g of yellow foam. The foam was triturated with pentane and 0.079 g (2896) of the title compound was collected as a white solid. mp 132°C. Analysis calculated for C"HsaCIN,O: C, 70.66; H, 6.42; N, 10.30.
Found: C, 70.91; H, 6.66; N, 10.50.
SUBSTITUTE SHEET (RULE 26) -61 _ Example 67 7-(4-Chlorobenzamidol-1-(4-ethyl-1-piperazinyl)-naphthalene A solution of 7-(4-chlorobenzamido)-1-(1-piperazinyi)-naphthalene (0.197 g, 5.39 mmol, the product of Example 12) in tetrahydrofuran (14 mL) was chilled to -78°C and butyllithium (0.454 mL, 1.13 mmol, 2.5 M) was added in three portions. The yellow solution was stirred 5 minutes, then ethyl iodide (0.045 mL, 0.566 mmol) was added and the reaction was allowed to warm to room temperature. The mixture was treated with saturated aqueous ammonium chloride and the solvent was removed at reduced pressure. The residue was taken up in methylene chloride and extracted with saturated aqueous sodium bicarbonate and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2.5 inches). Elution proceeded as follows: 7596 ethyl acetate / hexane (150 mL), nil; 9096 ethyl acetate / hexane (200 mL) and ethyl acetate (200 mL), 0.135 g of a light yellow foam. This foam was triturated with pentane and 0.112 g (5296) of the title compound was collected as a white powder. mp 173-174.5°C.
Analysis calculated for CI~H~,CIN,O: C, 70.13; H, 6.14; N, 10.67. Found: C, 70.21;
H, 6.32; N, 10.79.
Example 6f3 7-Amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (2.035 g, 5.07 mmol, preparation 4) in tetrahydrofuran (50 mL) was chilled to -78°C and butyllithium (2.03 mL, 5.07 mmol, 2.5 M) was added dropwise. The dark solution was stirred 10 minutes, then 1-t-butoxycarbonyl-3-pyrrolidinone (0.939 g, 5.07 mmol in 4 mL
tetrahydrofuran) was added dropwise with a 4 mL tetrahydrofuran rinse. The reaction was allowed to warm to room temperature and the solvent was removed. The residue was taken up in methylene chloride and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (1.5 x inches). Elution proceeded as follows: 596 ethyl acetate / hexane (700 mL), unweighed forrun; 10°~6 ethyl acetate / hexane (200 mL), nil; 259'° ethyl acetate l hexane (300 mL), 0.94 g of 7-dibenzylamino-1-( 1-t-butoxycarbonyl-3-hydroxy-3-pyrrolidinyl)-naphthalene as a yellow oil which was suitable for use without further purfication. A
sample crystallized from ethyl acetate had mp 114-117°C. 'H NMR d 7.69 (d, J =
9 Hz, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.51 (d, J = 2 Hz, 1 H), 7.42-7.33 (m, 8 H), 7.32-7.22 (m, 3 H, SUBSTITIftf SHEET (RULE 26) partially obscutred by NMR solvent), 7.21-7.06 (m, 2 H), 4.81 (t, J = 21 Hz, 4 H), 3.99 (sym m, 1 H), 3.75 (sym m, 1 H), 3.5&3.35 (m, 1 H), 3.34.17 (m, 1 H), 2.29-2.10 (m, 1 H). 2.o2-l.ae (m, 1 H), 1.90 (s, 1 H), 1.49 (s, s H).
A solution of 7-dibeniylamino-1-(1-t-butoxycartionyl~-hydroxy-3-pyrrolidinyl).
naphthalene (1.0 g, 1.97 mmol) in benzene (20 mL) was chilled on wet ice (precipitate) and Burgess salt (0.89 g, 3.74 mol) was added all at once. The mixture was heated to 55°C for 2 hours. The reaction was cooled and extracted with water and brine. The combined aqueous phase was back extracted with ethyl ncetate and the combined organic layer was dried over calcium sullate. The organic layer was concentrated onto silica gel and flash chromatographed (1 x 2.5 inches). Elution with 696 ethyl acetate /
hexane ( 1300 mL) gave 0.764 g (7996) of a brown solid which wns a mixture of two dehydration products which were used directly in the next reaction.
A slurry of lithium aluminum hydride (1.78 g, 46.92 mmol) in tetrahydroturan (220 mL) was chilled to 0°C and the product of the above reaction (5.75 g, 11.73 mmol) was added in tetrahydrofuran (10 mL with 2 x 10 mL rinses). The mixture was refluxed 5 hours, chilled to 0°C and carefully quenched with sodium sulfate decahydrate. The reaction was filtered and the filter cake was rinsed well with methylene chloride. The filtrate wns concentrated at reduced pressure and the residue was taken up In methylene chloride. The organic phase was washed with brine, dried, and concentrated to give 4.58 g of a brown oil which was n 2:1 mixture of olefinic products as judged by integration of the methyl singlet at 2.48 ppm (major) and 2.31 ppm (minor) from the NMR spectrum. The mixture was used directly in the next step.
A mixture of the product of the above reaction (4.58 g) and 2096 palladium hydroxide on carbon (4.7 g) in ethanol (161 mL) and acetic acid (161 mL) was hydrogenated at about 50 psi for 5.5 hours. The reaction was filtered through Celite and the filtrate was concentrated at reduced pressure. The residue was neutralized with 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, concentrated onto silica gel and flash chromatographed (2 x 3.25 inches). Elution proceeded as follows: ethyl acetate (200 mL), nil; 196 triethylamine / 196 methanol / ethyl acetate (500 mL) and 296 triethylamine / 296 methanol / ethyl acetate (500 mL), nil; 596 triethylamine / 596 methanol / ethyl acetate (500 mL) and 1096 triethylamine / 1096 methanol / ethyl acetate (400 mL), 0.90 g of the title compound as a brown oil. 'H NMR 6 7.66 (d, J = 8.5 Hz, 1 H), 7.56 (d, *Trade-mark WO 94/21619 ' _.
J = 8 Hz, 1 H), 7.41 (d, J = 7 Hz, 1 H), 7.24 (s, 1 H, partially obscurred by NMR
solvent), 7.19 (t, J = 7.5 Hz, 1 H), 6.94 (dd, J = 2.5, 8.5 Hz, 1 H), 4.20-3.96 (m, 1 H), 3.87 (br s, 2 H), 3.08 (t, J = 8.5 Hz, 1 H), 2.91-2.70 (m, 3 H), 2.45 (s, 3 H). This material was suitable for use without further purfication.
Example 69 7-Benzamido-1-( 1-methvi-3-pvrrolidinvl)-nachthalene A solution of 7-amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene (0.139 g, 0.615 mmol, product of Example 68) and triethylamine (0.103 mL, 0.738 mmol) in tetrahydrofuran (5 mL) was chilled to 0°C and benzoyl chloride (0.086 mL, 0.738 mmol) was added. The reaction was warmed to room temperature and stirred overnight.
The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic layer was washed with 0.5 N, sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1 x 2 inches). Elution proceeded as follows: 50% to 75% ethyl acetate / hexane (375 mL), nil; ethyl acetate (200 mL), nil; 296 triethylamine / 2% methanol / ethyl acetate (200 mL), 0.14 g of brown oil which partially crystallized. Recrystallization from ethyl acetate gave 0.058 g, (28%) of the title compound as white crystals. mp 137-145°C; 'H NMR d 8.57 (d, J = 2 Hz, 1 H), 8.06 (br s, 1 H), 7.95 (dd, J = 1.5, 8 Hz, 2 H), 7.86 (d, J = 9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.59-7.49 (m, 4 H), 7.40 (t, J = 7.5 Hz, 1 H), 4.15 (sym m, 1 H), 3.04 (t, J =
9 Hz, 1 H), 2.93-2.81 (m, 2 H), 2.80-2.68 (m, 1 H), 2.66-2.50 (m, 1 H), 2.47 (s, 3 H), 2.08-1.96 (m, 1 H). Analysis calculated for C~zHzzN~O: C, 79.97; H, 6.71; N, 8.48.
Found: C, 79.36; H, 6.72; N, 7.94.
Example 70 7-Amino-1-( 1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene A solution of 8-bromo-2-(dibenzylamino)-naphthalene (5.0 g, 12.0 mmol, preparation 4) in tetrahydrofuran (300 mL) was chilled to -78°C and butyllithium (5.0 mL, 12.5 mmol, 2.5 M) was added dropwise to generate a dark red solution. A
tetrahydrofuran solution (40 mL) of 1-t-butoxycarbonyl-R-prolinal (2.61 g, 13 mmol) was added dropwise with a 10 mL tetrahydrofuran rinse. The reaction was stirred an additional 10 minutes, then carbon disulfide (0.95 mL, 16 mmol, predried over calcium sulfate) was added. The reaction color changed from green to brown and finally to orange. After stirring 30 minutes at -78°C, methyl iodide (0.82 mL, 13 mmol) was added and the reaction was allowed to warm to ambient temperature and stir 2 hours.
SUBSTITUTE SHEET (RULE 26) Aqueous ammonium chloride and ether were added and the phases were separated.
The organic layer was washed with water end brine, dried over magnesium suftate, concentrated onto silica gel and flash chromatographed (2 x 6 Inches). Elution proceeded ns follows: 296 ether / hexane (1 L), unweighed impurity; 596 ether / hexane (1000 mL), 1096 ether / hexane (1000 mL), end 2096 ether / hexane (1000 mL), 5.74 g (7896) of the xanthate intermediate as a mixture of diastereomers which was used directly in the next step.
A solution of the xanthate from the above reaction (5.74 g, 9.37 mmol) in toluene (300 mL) was heated to reflux and AIBN (0.26 g) (AIBN=azo(bis) isobutyronitrile) and tributyltin hydride (11.7 mL, 43.5 mmol) were added in three portions first at initial reflux and then after 1 and 2 hours of retlux. The reaction was refluxed an additional 1.5 hours, cooled to room temperature and allowed to stir overnight. The reaction was concentrated onto silica gel and flash chromatographed (2 x 8 inches). Elution proceeded as follows: hexane (1000 mL), unweighed tin t 5 impurities; 296 ether / hexane (2 L) and 396 ether / hexane (2 L), unweighed impurities;
596 ether / hexane (3 L), 3.07 g (6596) o/ 7-dibenzylamino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)- naphthalene as a hard yellow-green foam.
A mixture of 7-dibenzylamino-1-(1-t-butoxycarbonyt-pyrrolidin-2-(R)-ylmethyl) naphthalene (0.68 g, 1.34 mmol) and 2096 palladium hydroxide on carbon (0.25 g) In ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 50 psi for 8 hours.
Additional 2096 palladium hydroxide on carbon (0.25 g) was added and hydrogenation was continued overnight. The catalyst (0.3 g) was added a ti~ird time and hydrogenation was continued 24 hours more. The reaction was filtered through celite'~
and the pad was washed with ethanol. The filtrate was concentrated and the residue was taken up in ether. This organic phase was extracted with saturated aqueous sodium bicarbonate, water and brine, then it was dried and concentrated to give 0.368 g (8496) of the title compound as a tan Loam. A sample recrystallized from ether /
hexane as a light tan solid had mp 157-158.5°C. Analysis calculated for C?°H76N10?:
C, 73.59; t-i, 8.03; N, 8.58. Found: C, 73.47; H, 7.93; N, 8.37.
The S enantiomer of the title compound of Example 70 was prepared using the same procedure set forth in Example 70, except that 1-t-butoxycarbonyl-(S)-prolinal was used in place of 1-t-butoxycarbonyl-(R)-prolinal.
*Trade-mark Example 71 7-L4-Chlorobenzamidol-1-(pvrrolidin-2-(Rl-ylmethyll-naphthalene A solution of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphtha) ene (0.10 g, 0.306 mmol, product of Example 70) and triethylamine (0.085 mL, 6.1 mmol) in tetrahydroturan (5 mL) was chilled to 0°C and 4-chlorobenzoyl chloride (0.043 mL, 0.338 mmol) was added. The mixture was allowed to warm to room temperature and stir 2 hours. Ether was added and the reaction was extracted with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was concentrated onto silica gel and flash chromatographed (1 x 6 inches).. Elution proceeded as follows:
2096 ether / hexane, unweighed forrun; 3096 ether / hexane (200 mL) 0.096 g (68°~6) of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene as a white powder. A sample recrystallized from ether / hexane had mp 136.5-137 ° C; (a]p - -75.4°, c = 0.195 (chloroform). Analysis calculated for C~,H~CINzO,:
C, 69.74; H, 6.29; N, 6.02. Found: C, 69.75; H, 6.00; N, 6.00.
To a solution of 7-(4-chlorobenzamido)-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylme thyl)-naphthalene (0.09 g, 0.19 mmol) in ether (10 mL) was added ether saturated with gaseous hydrogen chloride (27 mL) in portions over several hours. The mixture was stirred overnight and concentrated. The residue was triturated with ether and 0.063 g (8096) of the title compound was collected as a faint pink solid salt. mp 230-231.5 ° C;
[a]p = -46.8°, c = 0.280 (methanol). Analysis calculated for Cz=Hz,CINzO - HCI ~ 0.5 HzO: C, 64.39; H, 5.90; N, 6.83. Found: C, 64.49; H, 5.38; N, 6.70.
The S enantiomer of the title compound of example 71 was prepared using the same procedure set forth in Example 71, except that 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(S)-ylmethyl)-naphthalene was used in place of 7-(4-chlorobenzamido)-1-( 1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene.
Example 72 7-Formamido-1-(pyrrolidin-2-(Rl-ylmethyll-naphthalene hydrochloride A mixture of 7-amino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene (0.096 g, 0.294 mmol, product of example 70), triethylamine (0.055 mL, 0.395 mmol) and acetyl formyl anhydride (0.050 mL, 0.373 mmol) in tetrahydrofuran (5 mL) was refluxed 2 hours. Additional acetyl formyl anhydride (0.020 mL) was added and the reaction was stirred 1 hour more. The reaction was diluted with ether and extracted with water and brine. The organic phase was dried, concentrated, and flash SUBSTITUTE SHEET (RULE 26) ~ 1584~'~
~6-chromatographed on silica gel (1 x 4 inches). Elution proceeded as follows:
1096 ethyl acetate / hexane (100 mL), nil; 2096 ethyl acetate / hexane (350 mL), nil;
2596 ethyl acetate / hexane (750 mL), 0.076 g (7396) of 7-formamido-t-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene as a pale pink oil.
The oil from the above reaction (0.076 g, 0.214 mmol) was dissolved in ether and ether saturated with hydrogen chloride (10 mL) was added in 2 mL portions over 1 hour. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under a nitrogen stream and the residue was scurried in ether (20 mL).
The slurry was gently refluxed 1 hour and the materiel was triturated to yield the title compound as a light tan powder. mp 223.5-224°C; [aJo = -51.5°, c = 0.295 (methanol). Analysis calculated for C,eH,eN~O ~ HCI ~ 1.5 HzO: C, 60.47; H, 6.98; N, 8.81. Found: C, 60.65; H, 6.69; N, 8.72.
Examcle 73 7-Amino-1~1-piaerazinvll-nachthalene The product of Example 11 (7-benzamido-1-(1-piperazinyl)-naphthalene, (0.063 g, 0.19 mmol) was combined with hydrochloric acid in ethanol (4 mL) and refluxed 16 hours. The reaction was concentrated at reduced pressure and the residue was neutralized with 4 N sodium hydroxide and extracted with methylene chloride.
The organic phase was washed with brine, dried and concentrated to a tan solid (0.041 g).
The solid was recrystallized from ethyl acetate / hexane to give 0.020 g (4796) of the title compound as light tan crystals. mp 184-186°C. HRMS m/e calculated for C"H,~N,:
227.1419. Observed m/e 227.1405.
Example 74 7-(Imidazolo-f4.5-bl-pvridin-1-yll-1-(1-piperazinyl,)-naphthalene A two phase mixture of methylene chloride (50 mL) and water (100 mL) containing 7-amino-1-(1-piperazinyl)-naphthalene (5.05 g, 22.23 mmol) and sodium carbonate (2.36 g, 22.23 mmol) was treated with di-tert-butyl Bicarbonate (4.85 g, 22.23 mmol, in 40 mL methylene chloride) dropwise with a 10 mL methylene chloride rinse.
The reaction was stirred overnight, then the phases were separated. The organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1.5 x 3.5 inches). Elution proceeded as follows: 1096 ethyl acetate / hexane (700 mL), 1.6agof7-tert-butoxycarbonylamino-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as a yellow foam; 10°ro ethyl acetate / hexane (200 mL) and 3096 ethyl acetate / hexane SUBSTITUTE SHEET (RULE 26) -67.
(500 mL), 4.18 g of 7-amino-1-(4-tert-butoxycarbonyt-1-piperazinyl)-naphthalene as a brown foam which had ' H NMR d 7.67 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H), 7.35 (d, J = 2.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.01 (dd, J = 1, 7.5 Hz, 1 H), 6.95 (dd, J = 2.5, 8.5 Hz, 1 H), 3.90 (br s, 2 H), 3.05 (br s, 8 H), 1.51 (s, 9 H).
A mixture of 7-amino-1-(4-tent-butoxycarbonyl-1-piperazinyt)-naphthalene (0.523 g, 1.60 mmol, product of the above reaction), 2-chloro-3-nitropyridine-N-oxide (0.335 g, 1.92 mmol, product of preparation 5) and 4-dimethylaminopyridine (0.195 g, 1.60 mmol) in ethanol (40 mL) was refluxed 2 hours. The solvent was removed at reduced pressure and the residue was taken up in methytene chloride. The organic solution was washed with saturated aqueous sodium bicarbonate and brine and the aqueous washes were back extracted (5x) with methylene chloride. The combined organic phase was dried, concentrated onto silica get and flash chromatographed (1 x 3 inches). Elution proceeded as follows: 50% ethyl acetate / hexane (200 mL) and ethyl acetate / hexane (200 ml.), nil; 7096 ethyl acetate / hexane (100 mL) and ethyl acetate (300 mL), 0.458 g (61 %) of 7-(3-vitro-1-oxido~2-pyridylamino)-1-(4-tert-butoxycarbonyt-1-piperazinyl)-naphthalene as a dark red foam which was suitable for use without further purification. A sample recrystallized from ether / hexane as orange crystals had mp 191-193°C. Analysis calculated for C~,H~,NsOs: C, 61.92; H, 5.85; N, 15.04. Found: C, 61.59; H, 5.79; N, 14.54.
A mixture of 7-(3-vitro-1-oxido-2-pyridylamino)-1-(4-tert-butoxycarbonyl-t -pip erazinyl)-naphthalene (0.40 g, 0.86 mmol, product of the above reaction), ammonium formats (1.0 g, 17.2 mmol), and 10% palladium on carbon (0.15 g) in ethanol (30 mL) was refluxed 4 hour while continually returning sublimed ammonium formats back into the reaction. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was washed with water and brine, dried over calcium sulfate, and concentrated. The residue was flash chromatographed on silica gel (1 x 3 inches). Elution proceeded as follows: 2596 ethyl acetate /
hexane (100 mL), nil; 3596 ethyl acetate / hexane (250 mL), 0.25 g of product. The product was treated with activated carbon, filtered, and concentrated. The residue was recrystalfized trim ethyl acetate / ether to give 0.11 g (30%) of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl )-naphthalene as white crystals which were sensitive to air (turn brown on air exposure) and had mp 183-184°C. Analysis calculated for Cz4H~9N50z: C, 68.71; H, 6.97; N, 16.69. Found: C, 68.76; H, 6.58; N, 16.56.
SUBSTITUTE SHEET (RULE 26) WO 94/21619 ~ 1 a 8 45 7 PCT/US94/01206 ~8-A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tart-butoxycarbonyl-1-piperazinyl )-naphthalene (0.124 g, 0.296 mmol, product of the above reaction) and ethoxymethylenemalononitrile (0.47 g, 0.385 mmol) in isopropanol (7 mL) was refluxed 4 hour. Additional ethoxymethyienemalononitrile (0.035 g) was added and the reaction was refluxed overnight. The reaction was concentrated onto silica gel and flash chromatographed (1 x 3.5 inches). Elution proceeded as follows: 10% ethyl acetate / hexane (400 mL), nil; 20% ethyl acetate / hexane (300 mL), unweighed isopropoxymethylenemalononitrile; 20% ethyl acetate / hexane (50 mL) and 40%
ethyl acetate / hexane (300 mL), 0.082 g (65%) of 7-(imidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as a tan oily foam which was suitable for use as obtained which had'H NMR a 8.76 (d, J = 2 Hz, 1 H), 8.51-8.48 (m, 2 H), 8.20 (dd, J = 1.5, 8 Hz, 1 H), 8.04 (d, J = 9 Hz, 1 H), 7.84 (dd, J = 5, 8 Hz, 1 H), 7.65 (d, J =
8 Hz, 1 H), 7.49 (t, J = 8 Hz, 1 H), 7.36 (dd, J = 5, 8 Hz, 1 H), 7.17 (d, J =
7.5 Hz, 1 H), 4.20-3.30 (br coalesced signal, 4 H), 3.16 (br s, 4 H), 1.51 (s, 9 H).
A solution of 7-rmidazolo-[4,5-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl-1-pip erazinyl)-naphthalene (0.076 g, 0.177 mmol) in ethanol (6 mL) was treated with hydrogen chloride saturated dioxane (4 mL). The mixture was stirred 10 hours at room temperature and a fine precipitate formed. The solvent was removed at reduced pressure and the residue was dissolved in hot methanol and filtered. The filtrate was concentrated to about 4 mL at the boil and treated with ethanol (3 mL). The white crystals obtained on cooling were collected and washed with cold ethanol to give 0.022 g (3396) of the dihydrochloride of the title compound. mp > 250° C.
Analysis calculated for C=°H,~NS ~ 2 HCI: C, 59.71; H, 5.26; N, 17.41. Found: C, 59.72; H, 5.29; N, 16.62.
Example 75 7-(1 2 3-Triazolo-14,5-bl-yyridin-1-y~-1-(1-piperazinyl)-naphthalene A mixture of 7-(3-amino-2-pyridylamino)-1-(4-tart-butoxycarbonyl-1-piperazinyl )-naphthalene (0.038 g, 0.0906 mmol, intermediate of example 74) in 5% sulfuric acid (1.5 mL, precooled to 0°C) was treated with sodium nitrite (0.0066 g, 0.095 mmol) in water (0.1 mL) with a water rinse (2 x 0.1 mL). The heterogeneous mixture was stirred 40 minutes at 0°C. The reaction was diluted with ice and neutralized with 1 N sodium hydroxide. The reaction was extracted with methylene chloride and this organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated to yield 7-(1,2,3-triazolo-[4,5-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl- 1-SUBSTITUTE SHEET (RULE 26) piperazinyl)-naphthalene as a brown oil (0.034 g, 87%) which was suitable for use without purification. A sample treated with activated carbon in methylene chloride and then recrystallized from ether / hexane had mp 173-175°C. Analysis calculated for C~,H~eNaOz; C, 66.96; H, 6.09; N, 19.52. Found: C, 66.61; H, 6.18; N, 19.28.
A solution of 7-(1,2,3-triazolo-[4,6-b]-pyridin-1-yl)-1-(4-tart-butoxycarbonyl-piperazinyl)-naphthalene (0.075 g, 0.174 mmol, product of the above reaction) in ethanol (4~mL) was treated with hydrogen chloride saturated dioxane (4 mL) and the mixture was stirred at room temperature 10 hours. The solvent was removed at reduced pressure and the residue was dissolved in hot methanol. The methanol solution was filtered hot and the filtrate was concentrated at the boil to about 1 mL.
Yellow crystals formed on cooling. These crystals were collected to give 0.031 g (48%) of the hydrochloride the title compound. mp >250°C. Analysis calculated for C,~H,eNa HCI: C, 62.21; H, 5.22; N, 22.91. Found: C, 62.11; H, 5.11; N, 22.53.
Example 76 1-(4-Methylpiperazin-1-yll-7-(pyrimid-5-yl)naphthalene A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.250 g, 0.67 mmol), bis(triphenylphosphine)palladium[II] chloride (0.025 g, 0.036 mmol), 5-trimethylstannylpyrimidine (0.178 g, 0.74 mmol, from Preparation 6), triethylamine -(0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethylformamide (12.5 mL) was heated between 100°C to 115°C under nitrogen for 45 minutes. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica get (approximately 25 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide] to afford the title compound (0.060 g, 0.20 mmol, 29%) as a pale yellow foam: R, = 0.15 in 2096 methanol in ethyl acetate;
"C NMR (CDCI3) d 157.3, 155.0, 149.8, 134.6, 134.5, 130.8, 129.9, 129.0, 127.1, 124.0, 123.4, 122.1, 116.0, 55.4, 52.7, 45.9; LRMS (m/z, relative intensity) 304 (M+, 7), 240 (100), 225 (15), 196 (16), 169 (44), 155 (33), 141 (16); HRMS m/e calculated for C,9H~oN, 304.1690. Observed m/e 304.1689.
Example 77 7 (5-CYanopyrid-3-yl~~-1-l4-methylpigerazin-1-yl)naphthalene A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.527 g, 1.53 mmol), bis(triphenylphosphine)palladium[II] chloride (0.537 g, 0.77 WO 94/21619 ~ 15 8 4 5'~ PCT/US94101206 -7o-mmol), 5-cyano-3-trimethylstannylpyridine (0Ø450 g, 1.69 mmol, from preparation 7), triethylamine (1.02 mL, 7.34 mmol), lithium chloride (0.194 g, 4.59 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethytformamide (6 mL) was heated between 100°C to 115°C under nitrogen for 1.5 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 596 methanol in ethyl acetate to afford the title compound (0.170 g, 0.52 mmol, 34%) as a pale yellow foam: R, = 0.40 in 596 methanol in ethyl acetate; ' H (CD,OD) a 9.08 (d, J_=2.2 Hz, 1 H), 8.82 (d; J=2.2 Hz, 1 H), 8.43 (t, J_=2.0 Hz, 1 H), 8.36 (br s, 1 H), 7.92 (d, J=8.5 Hz, 1 H), 7.70 (dd, _ -J=1.8 and 8.5 Hz, 1 H), 7.57 (br d, J=8.2 Hz, 1 H), 7.44 (t, J=7.8 Hz, 1 H), 7.17 (d, J=7.3 Hz, 1 H), 3.20-3.00 (br s, 4H), 2.85-2.65 (br s, 4H), 2.40 (s, 3H);
LRMS (m/z, relative intensity) 328 (M', 100); HRMS m/e calculated for C=,HzoN, 328.1690.
Observed m/e 328.1715 Example 78 General procedure for the synthesis of (1-piperazinvllnaphthyl-7-vl ethers.
To a flame dried round bottom flask was added 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene (0.30 g, 1.23 mmol), anhydrous N,N-dimethylformamide (3 mL), and 6096 dispersion of sodium hydride in mineral oil (0.060 g; 1.47 mmol, 1.2 eq). The resulting suspension was heated for twenty minutes at 40° C, and the resulting reaction mixture was then allowed to cool to room temperature. A suspension of the appropriate alkylating agent or appropriate electrophile (1.35 mmol, 1.1 eq), anhydrous DMF (1 mL) and 6096 sodium hydride (0.075 grams 0.00183 moles) was then added slowly over minutes in three portions to the reaction mixture, and the resuwng mixture was heated at 80°C. The progress of the reaction was monitored by TLC, and reaction completion was determined by consumption of 7-hydroxy-1-(4-methyl-1-piperazinyl)naphthalene as determined by TLC. Upon determination of reaction completion, DMF was then removed in vacuo, and the residue was partitioned between methylene chloride (40 mL) and saturated sodium bicarbonate solution (40 mL). The organic layer was removed, dried (Na~SO,), and concentrated in vacuo. The resulting residue was purified by flash column chromatography using silica gel (15 grams) and elution with 12:1:0.04 (CHzCh:
methanol: NH,OH) to afford the title compound.
SUBSTITUTE SHEET (RULE 26~
_71 Usfng the above general procedure, the following compounds were prepared:
A. 2 (8 (Methylpiperazin-1-yl)napthalen-2-yioxylnicotinonitrile 2-Chloro-3-cyanopyridine was the electrophile. Chromatography afforded the title compound (3396) as an amorphous solid: HRMS m/e calculated for C~,H~°N~O
5 344.1637. Observed m/e 34.4.1618; "C NMR (CDCI,) d 46.2, 52.9, 55.6, 97.7, 114.6, 115.0, 115.7, 118.1, 121.1, 123.4, 125.8,129.9, 130.1, 132.7, 143.5, 149.6, 150.0, 151.5, 163.9.
Example 79 8 (4 Methylpiperazin 1 yl)naphthalene-2-carboxylic acid phenylamide To a flame dried 3-neck flask were added 7-trifluoromethylsulfonyloxy-t-(4-methylpiperazin-1-yl)naphthalen a (0.958, 2.54 mmol), aniline (0.35 mL, 3.81 mmol), and triethylamine (0.39 mi_, 2.79 mmol). A balloon of carbon monoxide provided a CO
atmosphere above the reaction mixture via the reflux condenser. The reaction contents were heated at 100 ° C for ten minutes. The solution was then cooled to 70 ° C, and bis(triphenylphosphine)palladium(II) chloride (0.036 g, .05 mmol, 2 mo196) was added to the reaction solution. The resulting reaction mixture was stirred at 100°C for 19 hours. Then the CO balloon was refilled with C0, additional triethylamine (approx. 0.5 mL) was added, and this mixture was stirred at 100°C for 5 hours. Ethyl acetate (25 mL) was added to the cooled reaction mixture, and this mixture was then filtered through Celitem. The filtrate was concentrated in vacuo. The residue was purified using flash column chromatography using silica gel (30 g) and elution with 596 methanol in ethyl acetate to afford the title compound (0.090 g, 1096) as an amorphous solid: R, _ 0.42 in 9:1:0.1 methylene chloride/methanol/ammonium hydroxide; HRMS m/e calculated for CzzHz,N,O 345.1843. Observed m/e 345.1873; "C NMR (CDCI,) a 46.0, 52.9, 55.4, 115.9, 120.3, 123.2, 123.3, 123.7, 124.6, 128.0, 128.1; 129.1, 131.5, 136.2, 138.1, 150.5, 167Ø
Example 80 8 (4 Methylpiperazin 1 yl)naphthalene-2-carboxylic acid 4-chlorobenzvlamide A mixture of 7-trifluoromethylsuHonyioxy-1-(4-methylpiperazin-1-yl)naphthalene (9.0 g, 24 mmol), bis (triphenylphosphine) palladium chloride (0.36 g, 0.51 mmol) and methanol (90 mL) was warmed to 60°C under a balloon of carbon monoxide for 96 hours. The reaction was cooled to room temperature and charged with additional catalyst (0.28g, 0.396 mmol). The mixture was again placed under a carbon monoxide SUBSTITUTE SHEET (RULE 2b~
WO 94/21619 21 ~ g 4 ~ ~ PCTIUS94101206 atmosphere and refluxed 40 hours. The reaction was cooled filtered and concentrated to a brown oil. This residue was flash chromatographed on silica gel (300 g).
Elution was 30: 1: 0.03 ethyl acetate, methanol, ammonium hydroxide to afford 2.7 g (39.5%) of methyl 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylate as a light yellow solid: tlc:
R, = 0.32 (10: 0.5: 0.05, ethyl acetate, methanol, ammonium hydroxide), "C NMR
a 167.36, 150.32,136.85. 128.64,128.39, 127.83, 126.58, 125.89,125.19,123.37, 115.57, 55.22, 52.33, 52.17, 45.54, HRMS m/e calculated for C"Hz°N=O~: 284.152.
Observed m/e: 284.1513.
A mixture of the above ester (1.56 g, 5.48 mmol), methanol (50 mL) and lithium hydroxide (1.15 g, 27.4 mmol) was refluxed 22 hours. The reaction was concentrated and the residual solid was treated with hydrochloric acid in dioxane (32.9 mL, 32.9 mmol, 1 N). Water (3 mL) was added to yield a clear solution which was concentrated in vacuo to afford 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylic acid hydrochloride as a solid which also contained lithium hydrochloride. This material was used without purification and assumed to be a quantitative yield reaction. HRMS m/e calculated for C,eH"N=O=: 270.1370. Observed m/e: 270.1360.
A mixture of the above acid (0.25 g, 0.82 mmol), methylene chloride (4 mL), N-methylmorpholine (0.31 mL, 2.87 mmol), 1-hydroxy benzotriazole hydrate (0.12 g, 0.9 mmol), 4-chlorobenzylamine (0.1 mL, 0.82 mmol) and 1-cyclohexyl-3-(7-morpholinoethyl) carbodiimide p-toluenesulfonate (0.69 g, 1.62 mmol) was stirred 17 hours at ambient temperature. The reaction was diluted with water (10 mL) and methylene chloride (10 mL) and adjusted to pH 9 by addition of saturated aqueous sodium carbonate. The phases were separated and the organic layer was dried over sodium sulfate and concentrated to a yellow solid. This material was purfied by flash chromatography on silicon gel (6 g). Elution with 12: 1: 0.04, metnyiene crnonae, methanol, ammonium hydroxide gave 0.07 g (21.8%) of the title compound as a solid:
mp 72-74°C; tlc: R, = 0.28 (12: 1: 0.04, methylene chloride, methanol, ammonium hydroxide); "C NMR d 168.04, 150.69, 137.09, 136.16, 133.17, 130.82, 129.01, 128.90, 128.77, 128.18, 127.91, 123.84, 123.30, 123.07, 115.61, 55.47, 53.10, 46.13, 43.34.
HRMS m/e calculated for Cz,Hz,CIN,O: 393.1607. Observed m/e: 393.1642.
SUBSTIME SHEET (RULE 26) ~8 45'x -73-ExamDIe 81 7 (3-Methoxyphenvl)-1-(4-methylDioerazin-1-yl)naphthalene A mixture of 3-methoxy-1-bromobenzene (0.089 mL, 0.71 mmol), 7 trimethylstannyl-1-(4-methylpiperazin-1-yl)naphthalene (0.25 g, 0.64 mmol), bis (acetonitrile) palladium chloride (0.0085 g, 0.032 mmol), tri(3-methoxyphenyi)phosphine (0.023 g, 0.064 mmol), and butylated hydroxytoluene (BHT, about 0.001 g, antioxidant) in dimethyl formamide (12 mL) was warned to 110°C for 2 hours. The reaction was cooled to room temperature and diluted with 1 N aqueous lithium chloride (25 mL) and 1 N sodium hydroxide (2 mL); then extracted with ether (3X). The combined ether layer was washed with 1 N aqueous lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was purfied by flash chromatography on silica gel (1x2.5 inches). Elution proceeded as follows:
7596 ethyl acetate / hexane, 200 mL, nil; 296 methanol / ethyl acetate 200 mL and 1096 methanol / ethyl acetate, 200 mL, 0.084 g of an oil. This oil was further purled by kugelrohr distillation (1 mm Hg). The distillation proceeded as follows: 110-130°C, 0.014 g of a mixture of the title product and 7-methyl-1-(4-methylpiperazin-1-yl)naphthalene: 200-220°C, 0.062 g (2396) of the title compound as a yellow oil: 'H NMR d 8.43 (incompletely resolved dd, J = 1.2Hz, 1 h), 7.90 (d, J = 9 Hz, 1 H), 7.74 (dd, J = 2, 8.5 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H), 7.43 (sym m, 2 H), 7.34 (dt, J = 1.5, 7.5 Hz, 1 H), 7.29 (5, J = 2 Hz, 1 H), 7.14 (dd, J = 1, 7.5 Hz, 1 H), 6.96 (ddd, J = 1, 2.5, 8 Hz, 1 H), 3.92 (s, 3 H) 3.20 (br s, 4 H), 2.75 (br s, 4 H), 2.44 (s, 3 H). The product was dissolved in chloroform and HCL gas was bubbled through the solution to form the hydrochloride salt. Concentration of this solution to about 1 mL. at the boil and addition of about 1 mL of ether caused the white crystalline product to precipitate. The hydrochloride salt weighted 0.057 g: mp 236-238°C. Analysis calculated for C~ZH~,NzO ~
HCI: C, 71.63;
H, 6.83; N, 7.59. Found: C, 71.31; H, 6.92; N, 7.59.
Example 82 1 (1 Methylpiperidin-4-yl)-7-naphthalene carboxylic acid 4-chlorobenzylamide A mixture of 1-(1-methylpiperidin-4-yl)-7-trifluoromethylsuifonytoxynaphthalene (1.0 g, 2.69 mmol), 4-chlorobenzylamine (0.59 mL, 4.84 mmol) and bis (triphenylphosphine)palladium chloride (0.095 g, 0.13 mmol), and triethylamine (0.56 mL, 4.04 mmol) was blanketed with an atmosphere of carbon monoxide (with the aid of a balloon) and heated to 110-120°C for 2 hours. Additional 4-chlorobenzylamine SUBSTITUTE SHEET (RULE 26) (0.2 mL) was added and the reaction was heated under carbon monoxide for 17 hours more. The reaction was cooled to room temperature and taken up in ethyl acetate.
The mixture was extracted with water and brine, dried over caldum sulfate, and concentrated. The residue was flash chromatographed on silica gel (1.5 x 2.5 inches).
Elution proceeded as follows: ethyl acetate, 350 mL, nil; 296 methanol / ethyl acetate, 300 mL, nil; 496 methanol / 196 triethylamine / ethyl acetate, 200 mL, 0.085 g of impure product. Continued elution with 496 methanol / 196 triethylamine / ethyl acetate, 200 mL, 0.266 g (2596) of the title compound as a yellow oil. 'H NMR (DMSOda) 6 8.74 (s, 1 H), 7.90 (d, J=8.5 Hz, 1 H), 7.73 (dt, J=1.5, 8.5 Hz, 2H), 7.58-7.48 (m, 2H), 7.35 (s, 4H), 6.63 (br t, J=6 Hz, 1 H), 4.70 (d, J=6 Hz, 2H), 3.42 (quintuplet, J=8 Hz, 1 H), 3.05 (br d, J=12 Hz, 2H), 2.38 (s, 3H), 2.23 (sym m, 2H), 1.99-1.92 (m, 4H). HRMS
m/e calculated for C~,H~C1 NzO: 393.1733. Observed m/e: 393.1747.
Synthesis of intermediates used in the above Examples are described in the preparations below.
Preparation 1 7-hydroxy-1-(4-methyl-1-piperazinyly-3.4-dihydronaphthalene 7-Hydroxy-a-tetralone (1.0 g, 6.17 mmol, Corey and Estreicher, Tetrahedron Lett., 1981, 22, 603) and 1-methylpiperazine (2.2 mL, 19.83 mmol) were dissolved in dry THF (90 mL) and chilled to 0°C. Titanium tetrachloride (0.91 mL, 8.3 mmol) was allowed to run down the side of the reaction vessel into the reaction via syringe to give a vigorous reaction which caused the solution to tum orange-red. The mixture was allowed to warm to ambient temperature and stir 1.5 hours. A 2:1 mixture of water and concentrated ammonium hydroxide (90 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried over calcium sulfate and concentrated to give 1.48 g of crude enamine which was used immediately without characterization.
(This enamine was not stable to chromatography but did show a characteristic signs!
in the 'H NMR for the enamine vinyl proton at 5.28 ppm with a 4.7 Hz coupling constant).
Preparation 2 7-Hydroxy-1-(4-meth5rl-1-piperazinyl~~-naphthalene 1096 Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene (1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture was cooled, filtered, and concentrated. The product was purified SUBSTITUTE SHEET (RULE 26) by flash chromatography on silica gel (1 x 6 inches). Elution with 50 96 ethyl acetate/hexane followed by 10096 ethyl acetate gave 0.51 g (3496) of the title product as a light pink foam. A sample was recrystallized from ether to give a seam colored solid for analysis: mp 184-185°C. Analysis calculated for C,6H,eN=O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05; H, 7.03; N, 11.42.
Preparation 3 7 Trimethylstannvl-1-(4-methyl-1-piperazinyll-naahthalene 7-trifluoromethylsulfonyloxy-1-(4-methyl-1-piperazinyl)-naphthalene (2.0 g, 5.34 mmol), hexamethylditin (1.92 g, 5.86 mmol), lithium chloride (0.68 g, 16 mmol), tetra (triphenylphosphine) palladium (0.24 g, 0.21 mmol) and butylated hydroxytoluene (a few crystals, antioxidant) were combined in dry dioxane (50 mL) and refluxed 45 minutes.
The mixture was cooled and quenched with saturated ammonium chloride (50 mL).
The mixture was extracted with ether (2x) and the combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated to a brown oil.
Flash chromatography on silica gel (2 x 4 inches) with 5096 ethyl acetate/hexane elution gave 0.77 g (3796) of the title product as a light brown oil which slowly solidified. The product was suitable for use in subsequent reactions but was not analytically pure:'H
NMR d 8.36 (s with Sn coupling, 1 H), 7.80 (d, J_ = 8 Hz, 1 H), 7.61-7.51 (m, 2H), 7.40 (t, J = 8 Hz, 1 H), 7.09 (dd, J = 1, 7.5 Hz, 1 H), 3.2 (br s, 4H), 2.75 (br s, 4H), 2.46 (s, 3H), 0.39 (s with Sn coupling of 55.0 and 52.5 Hz, 9H).
Preparation 4 8-Bromo-2-(dibenzylamino)-naphthalene A mixture of dibenzylamine (70.8 mL, 0.368 mol), 8-bromo-2-tetralone (82.86 g, 0.368 mol, U. S. patent 4,897,405 A), dry toluene (1000 mL), and p-toluenesulfonic acid (0.83 g, 4.36 mmol) was refluxed 2 days with azeotropic removal of water. Most of the toluene was distilled away from the reaction and the residual material was dried in vacuo about 12 hours. The crude enamine was obtained as an orange oil and was used directly in the next step. 'H NMR d 7.41-7.17 (m, 13 H), 6.97 (d, J = 7.3 Hz, 1 H), 6.72 (t, J = 7.6 Hz, 1 H), 5.83 (s, 1 H), 4.54 (s, 4 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.55 (dd, J = 8.5, 6.6 Hz, 2 H).
The enamine from the above reaction was dissolved in tetrahydrofuran (2000 mL) and chilled to 0°C. Chloranil (90.48 g, 0.368 mol) was added in portions over 10 minutes. The black solution was stirred 1.45 hours at 0°C, then the solvent was SUBSTITUTE SHEET (RULE 26) ~'~58457 removed at reduced pressure. Tha residua was taken up in methylene chloride (760 mL) and filtered through Cattle to remove an insoluble yellow material (discarded).
Saturated sodium carbonate (600 mL) was added to the filtrate and the two phase mixture was vigorously stirred 15 minutes. The mixture was again filtered tfttoughC~lite*
to remove a greenish solid (discarded). Tt~e phases were separated from the filtrate and the organic layer was washed with saturated sodium carbonate and then brine.
The solution was dried over calcium sulfate end concentrated onto silica gel and applied to a flash chromatography column (4 x 4 Inches silica gel). Elution proceeded as follows: hexane (500 mL, n11); 596 ether / hexane (2 L, nil); b% ether /
hexane (12 L, unweighed orange oil product). The oil was triturated with 5096 ett~er:hexane (500 mL) to yield the tan product, 8-bromo-2-(dibenzylamino)-naphthalene (72.15 g).
The residues from the trituration were rechromatographed as above to afford an additional 18.95 g of product. The combined yield was 91.1 g, 61%. mp 102.5-103°C;'H NMR
d 7.64-7.60 (m, 3 H), 7.37-7.24 (m, 11 H), 7.13 (dd, J = 9, 2.6 Hz, 1 H), 7.00 (t, J = 7.8 Hz, 1 H), 4.80 (s, 4 H). Analysis calculated for C"H,°8rN: C, 71.65; H, 5.01; N, 3.48.
Found: C, 71.24; H, 4.65; N, 3.49.
Preparation 6 2-Chloro-3-nitropyridine-N-oxide 2-Chloro-3-nitropyridine (0.69 g, 4.35 mmol) was chilled to 0°C and trifluoroacetic acid (9 mL) was slowly added followed by 3096 hydrogen peroxide (1 mL). The solution was warmed to 70°C for 1.5 hours, cooled to 0°C and excess peroxide was decomposed by dropwise addition of dimelhylsutfide (1 mL) and stirring 0.5 hours. The reaction was concentrated at reduced pressure onto silica gel and (lash chrornatographed (1 x 3 inches). Elution proceeded as follows: 5096 ethyl acetate /
hexane (175 mL), nil; 7596 ethyl acetate / hexane (175 mL), 0.589 g (7796) of 2-chloro-3-nitropyridine-N-oxide as an orange solid suitable for use without further purification. A
sample recrystallized from ethyl acetate / hexane had mp 98-100°C.
Analysis calculated for CSH~CINzO~: C, 34.41; H, 1.73; N, 16.05. Found: C, 34.75; ti, 1.67; N, 15.80.
*Trade-mark 2~y5~ ~~~
-n.
Preparation 6 5-Trimethylstenn~rlp~rrimidine A mixture of 5-bromopyrimidine (4.00 g, 25.16 mmol), hexamethylditin (9.06 g, 27.67 mmol), lithium chloride (1.27 g, 30.19 mmol), tetrakis(triphenylphosphine) palladium (1.13 g, 0.981 mmol), 2,6-di-tert-butyl-methylphenol (approximately 0.01 g), and dioxane (45 mL) was heated at reflux under nitrogen for 7 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 200 g) and elution with ethyl acetate/hexanes [1:1 J to afford the title compound (4.75 g, 19.6 mmol, 78%) as a clear, colorless liquid: R, = 0.6 in ethyl acetate/hexanes [1:1 J;'H NMR (CDCI,) a 9.11 (s, 1 H), 8.70 (s, 2H), 0.38 (s, 9H); "C NMR (CDCh) d 162.8, 158.5, 134.4, -9.6.
Preparation 7 5-Cyano-3-trimethylstannylpyridine A mixture of 3-bromo-5-cyanopyridine (5.84 g, 31.91 mmol), hexamethylditin (11.49 g, 35.10 mmol), lithium chloride (1.62 g, 38.29 mmol), tetrakis(triphenylphosphine)palladium (1.44 g, 1.24 mmol), 2,6-di-tert-butyl-4 methylphenol (approximately 0.01 g), and dioxane (60 mL)was heated at reflux under nitrogen for 8 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 200 g) and elution with ether/hexanes [1:1 J to afford the title compound (1.98 g, 7.41 mmol, 23%) as a pale yellow solid: mp, 77.0-79.0°C; R, =
0.65 in ether/hexanes [1:1J; 'H NMR (CDCI,) a 8.80 (dd, J=1.5 and 2.4 Hz, 2H), 8.03 (dd, J=1.5 and 2.1 Hz, 1 H), 0.39 (s, 9H).
The compounds of formula I of the present invention described in the above Examples were assayed for 5-HT", and 5-HT,° affinity using the aforementioned procedures with ICSOs of less than 0.60 NM for at least one of the above affinities.
SUBSTITUTE SHEET (RULE 26~
Claims (24)
1. A compound of the formula:
(where R1 is a group of the formula:
R2 is -R4, -O-R4, -O-S(O)2-R4, -NR4R6, - (CH2) c- (C=X)NH- (CH2)b-R4, -NH(C=O)-(CH2)c-NH(C=O)O-(CH2)b-R4, -NH(C=O)-NH(C=O)-R4, -(CH2)b-NH(C=X)-(CH2)c-R4, -(CH2)c-(C=O)O-(CH2)b-R4, -(CH2)b-O(C=O)-(CH2)c-R4, -NH(C=X)NH-R4, -O(C=O)O-R4, -O(C=O)NH-R4, -NH(C=O)O-R4.
-(CH2)b-(C=O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5.
-CH(OH)-R4, -(C=O)-NR4R5, -CN, -NO2, substituted C1 to C6 alkyl, substituted or unsubstituted C2 to C6 alkenyl, or substituted or unsubstituted C2 to C6 alkynyl, the substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4 or -S(O)d-R4;
R3 is hydrogen, CH3OCH2CH2, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl;
R4 and R5 are each independently hydrogen, -CF3, C1 to C6 alkyl, C1 to C6 alkylaryl, with the proviso that when R2 is -R4 or -OR4, R4 is not hydrogen or C1 to C6 alkyl;
R6, R7, R8, R9. R10, R11, R12, R13, R14, R15, R16, R17, and R18 are each independently H, halogen, -CF3, -(C=O)R20, -CN, -OR20, -NR20R21, -NR20SO2R22, -N=C=N(CH3)2, -N20CO2R22, -S(O)eR20, -SO2NR20R21, -NO2, aryl, C1 to C6 alkylaryl, -(C=O)OR20, -(C=O)NR20R21, C1 to C6 alkyl, C2 to C6 alkenyl, and C2 to C6 alkynyl;
R6 and R7, R7 and R8, R8 and R9, R9 and R10, R11 and R12, R12 and R13, R13 and R14, R15 and R16, R16 and R17, and R17 and R18 may be taken together to form a five-to seven-membered alkyl ring, a six-membered aryl ring, a five-to seven-membered heteroalkyl ring having one heteroatom of N, O, or S, or a five-to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S;
M is C, N, C=O or C-O;
R19 is hydrogen or C1 to C3 alkyl when M is C, N or C-O
and R19 is absent when M is C=O;
R20 and R21 are each independently hydrogen, C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl, or may be taken together to form a C4 to C7 alkyl ring;
R22 is C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl;
A, B, D, E and F are each independently C or N;
G, I, J, and K are each independently C, N, O, S, or (C=O), with the proviso that there is at most one of O, (C=O), or S per ring;
L and Z are each independently C or N;
X is O or S;
a is 0, 1 or 2;
e is 0, 1 or 2;
d is 0, 1, or 2;
b and c are each independently 0, 1, 2, 3, 4, 5, or 6, with b+c being at most 6;
a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein the substituted phenyl is substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C1 to C4 alkoxy), or a pharmaceutically acceptable salt thereof.
(where R1 is a group of the formula:
R2 is -R4, -O-R4, -O-S(O)2-R4, -NR4R6, - (CH2) c- (C=X)NH- (CH2)b-R4, -NH(C=O)-(CH2)c-NH(C=O)O-(CH2)b-R4, -NH(C=O)-NH(C=O)-R4, -(CH2)b-NH(C=X)-(CH2)c-R4, -(CH2)c-(C=O)O-(CH2)b-R4, -(CH2)b-O(C=O)-(CH2)c-R4, -NH(C=X)NH-R4, -O(C=O)O-R4, -O(C=O)NH-R4, -NH(C=O)O-R4.
-(CH2)b-(C=O)-(CH2)c-R4, -NH-S(O)2-R4, -C(OH)R4R5.
-CH(OH)-R4, -(C=O)-NR4R5, -CN, -NO2, substituted C1 to C6 alkyl, substituted or unsubstituted C2 to C6 alkenyl, or substituted or unsubstituted C2 to C6 alkynyl, the substituted moieties substituted with a moiety of the formulae -R4, -R4R5, -O-R4 or -S(O)d-R4;
R3 is hydrogen, CH3OCH2CH2, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl;
R4 and R5 are each independently hydrogen, -CF3, C1 to C6 alkyl, C1 to C6 alkylaryl, with the proviso that when R2 is -R4 or -OR4, R4 is not hydrogen or C1 to C6 alkyl;
R6, R7, R8, R9. R10, R11, R12, R13, R14, R15, R16, R17, and R18 are each independently H, halogen, -CF3, -(C=O)R20, -CN, -OR20, -NR20R21, -NR20SO2R22, -N=C=N(CH3)2, -N20CO2R22, -S(O)eR20, -SO2NR20R21, -NO2, aryl, C1 to C6 alkylaryl, -(C=O)OR20, -(C=O)NR20R21, C1 to C6 alkyl, C2 to C6 alkenyl, and C2 to C6 alkynyl;
R6 and R7, R7 and R8, R8 and R9, R9 and R10, R11 and R12, R12 and R13, R13 and R14, R15 and R16, R16 and R17, and R17 and R18 may be taken together to form a five-to seven-membered alkyl ring, a six-membered aryl ring, a five-to seven-membered heteroalkyl ring having one heteroatom of N, O, or S, or a five-to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S;
M is C, N, C=O or C-O;
R19 is hydrogen or C1 to C3 alkyl when M is C, N or C-O
and R19 is absent when M is C=O;
R20 and R21 are each independently hydrogen, C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl, or may be taken together to form a C4 to C7 alkyl ring;
R22 is C1 to C6 alkyl, aryl, or C1 to C6 alkylaryl;
A, B, D, E and F are each independently C or N;
G, I, J, and K are each independently C, N, O, S, or (C=O), with the proviso that there is at most one of O, (C=O), or S per ring;
L and Z are each independently C or N;
X is O or S;
a is 0, 1 or 2;
e is 0, 1 or 2;
d is 0, 1, or 2;
b and c are each independently 0, 1, 2, 3, 4, 5, or 6, with b+c being at most 6;
a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein the substituted phenyl is substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, vitro, and C1 to C4 alkoxy), or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1, wherein R1 is formula II; R2 is -R4, -OR4, -(CH2)c-(C=X)NH-(CH2)b-R4, or -(CH2)b-NH(C=O)-(CH2)c-R4; R3 is hydrogen or C1 to C6 alkyl;
R4 is formula XV or formula XVII; A, B, D, E and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN, or -OR20;
and R20 is C1 to C6 alkyl.
R4 is formula XV or formula XVII; A, B, D, E and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN, or -OR20;
and R20 is C1 to C6 alkyl.
3. The compound or salt of claim 1, wherein R1 is formula III; R2 is -R4, -OR4, -(CH2)2-(C=X)NH-(CH2)b-R4 or -(CH2)b-NH(C=O)-(CH2)c-R4; R4 is formula XV or formula XVII;
R3 is hydrogen or C1 to C6 alkyl; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN , or -OR20;
and R20 is C1 to C6 alkyl.
R3 is hydrogen or C1 to C6 alkyl; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN , or -OR20;
and R20 is C1 to C6 alkyl.
4. The compound or salt of claim 1, wherein R1 is R2 is -R4, -OR4, -(CH2)2-(C=X)NH-(CH2)b-R4 or -(CH2)b-NH(C=O)-(CH2)c-R4; R3 is hydrogen or C1 to C6 alkyl;
R4 is formula XV or formula XVII; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN , or -OR20;
and R20 is C1 to C6 alkyl.
R4 is formula XV or formula XVII; A, B, D, E, and F are each independently C or N; R6, R7, R8, R9, R10, R15, R16, R17 and R18 are each independently hydrogen, halogen, -CN , or -OR20;
and R20 is C1 to C6 alkyl.
5. The compound or salt of claim 1, wherein R1 is formula II, formula III, or formula IV; R2 is -R4; R3 is hydrogen or C1 to C6 alkyl; R4 is formula XVI; G, I, J, and K
are each independently C, N, or O; L is C; R11, R12, R13, and R14 are each independently hydrogen, C1 to C6 alkyl, or C1 to C6 alkylaryl.
are each independently C, N, or O; L is C; R11, R12, R13, and R14 are each independently hydrogen, C1 to C6 alkyl, or C1 to C6 alkylaryl.
6. 7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(1-methylpyrrolidin-3-yl)naphthalene.
7. 7-(4-Chlorobenzamido)-1-(pyrrolidin-2-(R)-ylmethyl)naphthalene.
8. 2-[8-(4-Methylpiperazin-1-yl)naphthalen-2-yloxy]nicotinonitrile.
9. 1-(4-Methylpiperazin-1-yl)-7-pyrimidin-5-yl)naphthalene.
10. 7-(5-Cyanopyridin-3-yl)-1-(4-methylpiperazin-1-yl)naphthalene.
11. 1-(Piperazin-1-yl)-7-(pyrimidin-5-yl)naphthalene.
12. 7-(4-Chlorobenzamido-1-(4-methylpiperazin-1-yl)naphthalene.
13. 7-(3-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene.
14. 7-(Imidazolo[4,5-b]pyridin-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene.
15. 8-(4-Methylpiperazin-1-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide.
16. 7-(4-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene.
17. 7-Pyrimidin-2-yloxy-1-(4-methylpiperazin-1-yl)naphthalene.
18. 7-(Benzimidazol-1-yl)-1-(4-methylpiperazin-1-yl)naphthalene.
19. 8-(1-Methylpiperidin-4-yl)naphthalene-2-carboxylic acid 4-chlorobenzylamide.
20. A pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, Alzheimer's disease, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof effective in treating such condition arid a pharmaceutically acceptable carrier.
21. A pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission comprising at amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carrier.
22. A process for producing a compound of the formula I
as defined in claim 1 in which R1 is of the formula:
which comprises reacting an .alpha.-tetralone of the formula:
(wherein R2 is as defined in claim 1) with a piperizene compound of the formula:
(wherein R3 is as defined in claim 1) in the presence of an acid catalyst in a reaction inert solvent, to form an enamine of the formula:
(wherein R2 and R3 have the meanings given above) oxidizing the enamine in a reaction inert solvent, to form the desired compound of the formula:
(wherein R2 and R3 have the meanings given above).
as defined in claim 1 in which R1 is of the formula:
which comprises reacting an .alpha.-tetralone of the formula:
(wherein R2 is as defined in claim 1) with a piperizene compound of the formula:
(wherein R3 is as defined in claim 1) in the presence of an acid catalyst in a reaction inert solvent, to form an enamine of the formula:
(wherein R2 and R3 have the meanings given above) oxidizing the enamine in a reaction inert solvent, to form the desired compound of the formula:
(wherein R2 and R3 have the meanings given above).
23. The process according to claim 22, wherein the oxidation of the enamine of the formula VII is carried out by a catalytic oxidation using a noble metal catalyst or by a chloranil or elemental sulfur oxidation.
24. A compound of the formula:
wherein R1 is of the formulae R2 is (Methyl)3Sn- or (Butyl)3Sn-, R3 is hydrogen, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl; a is 0, 1, or 2; and a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy.
wherein R1 is of the formulae R2 is (Methyl)3Sn- or (Butyl)3Sn-, R3 is hydrogen, C1 to C6 alkyl, C1 to C6 alkylaryl, or aryl; a is 0, 1, or 2; and a broken line indicates the presence optionally of a double bond and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3204293A | 1993-03-16 | 1993-03-16 | |
| US08/032,042 | 1993-03-16 | ||
| PCT/US1994/001206 WO1994021619A1 (en) | 1993-03-16 | 1994-02-15 | Naphthalene derivatives |
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|---|---|
| CA2158457A1 CA2158457A1 (en) | 1994-09-29 |
| CA2158457C true CA2158457C (en) | 2001-04-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| JP (1) | JP2810236B2 (en) |
| AT (1) | ATE201403T1 (en) |
| AU (1) | AU6391894A (en) |
| CA (1) | CA2158457C (en) |
| DE (1) | DE69427289T2 (en) |
| DK (1) | DK0689536T3 (en) |
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| IL (1) | IL108923A0 (en) |
| PT (1) | PT689536E (en) |
| WO (1) | WO1994021619A1 (en) |
| ZA (1) | ZA941806B (en) |
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| MX9700080A (en) * | 1994-06-29 | 1997-04-30 | Pfizer | Aryl and heteroaryl alkoxynaphthalene derivatives. |
| US5597826A (en) | 1994-09-14 | 1997-01-28 | Pfizer Inc. | Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist |
| FR2725984B1 (en) * | 1994-10-25 | 1997-01-10 | Pf Medicament | NOVEL AROMATIC ETHERS DERIVED FROM NAPHTYLPIPERAZINE USEFUL AS MEDICINES |
| US5472966A (en) * | 1995-03-29 | 1995-12-05 | Bristol-Myers Squibb Company | Antidepressant heteroarylaminoalkyl derivatives of naphthyl-monazines |
| EP0795328A1 (en) * | 1996-03-15 | 1997-09-17 | Pfizer Inc. | Use of naphthalene derivatives in treating lung carcinoma |
| SE9601110D0 (en) * | 1996-03-22 | 1996-03-22 | Astra Ab | Substituted 1,2,3,4-tetrahydronaphthalene derivatives |
| PT810220E (en) * | 1996-05-28 | 2002-04-29 | Pfizer | ARILACRYLAMIDE DERIVATIVES AS 5HT1 AGONISTS OR ANTIGONISTS |
| US6423708B1 (en) | 1996-09-30 | 2002-07-23 | Pfizer Inc | Aralkyl and aralkylidene heterocyclic lactams and imides |
| UA56185C2 (en) | 1996-09-30 | 2003-05-15 | Пфайзер Інк. | Aralkyl- and aralkylidene heterocyclic lactams and imids, a pharmaceutical composition and a treatment method |
| EP0946551A2 (en) * | 1996-12-19 | 1999-10-06 | Smithkline Beecham Plc | N-piperazin-1-ylphenyl-benzamide derivatives |
| SE9900190D0 (en) | 1999-01-22 | 1999-01-22 | Astra Ab | New compounds |
| SE9702799D0 (en) | 1997-07-25 | 1997-07-25 | Astra Ab | New compounds |
| SE9703379D0 (en) | 1997-09-18 | 1997-09-18 | Astra Ab | New compounds |
| EP0943333A1 (en) * | 1998-03-18 | 1999-09-22 | S.W. Patentverwertungs GmbH | Medicament for the prevention and/or treatment of breast cancer comprising an inhibitor of estrogen synthesis |
| ATE228119T1 (en) | 1998-04-15 | 2002-12-15 | Pfizer Prod Inc | HETEROCYCLIC CARBOXAMIDES |
| GB9926301D0 (en) * | 1999-11-05 | 2000-01-12 | Smithkline Beecham Plc | Novel compounds |
| GB9926302D0 (en) * | 1999-11-05 | 2000-01-12 | Smithkline Beecham Plc | Novel compounds |
| YU98003A (en) | 2001-06-11 | 2006-03-03 | Biovitrum Ab. | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
| SE0103644D0 (en) * | 2001-11-01 | 2001-11-01 | Astrazeneca Ab | Therapeutic isoquinoline compounds |
| EP1450806B1 (en) | 2001-11-09 | 2009-04-29 | Biovitrum AB (publ) | Use of sulfonamide derivatives in the treatment of obesity or for the reduction of food intake |
| US7943639B2 (en) | 2002-06-20 | 2011-05-17 | Proximagen Limited | Compounds |
| AU2003243091A1 (en) * | 2002-06-20 | 2004-01-06 | Biovitrum Ab (Publ) | New compounds useful for the treatment of obesity, type ii diabetes and cns disorders |
| EP1689721B1 (en) | 2003-11-26 | 2010-07-14 | Pfizer Products Inc. | Aminopyrazole derivatives as gsk-3 inhibitors |
| WO2005090300A1 (en) | 2004-03-17 | 2005-09-29 | Pfizer Products Inc. | Novel benzyl(idene)-lactam derivatives |
| DE102004014304A1 (en) * | 2004-03-22 | 2005-10-06 | Grünenthal GmbH | Substituted 1,4,8-triazaspiro [4,5] decan-2-one compounds |
| WO2006062481A1 (en) * | 2004-12-09 | 2006-06-15 | Biovitrum Ab | New benzofuran derivatives and their use in the treatment of obesity, type ii diabetes and cns disorders . |
| WO2011163355A1 (en) | 2010-06-24 | 2011-12-29 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compounds as phosphodiesterases (pdes) inhibitors |
| JP6006009B2 (en) * | 2012-06-14 | 2016-10-12 | ユー・ディー・シー アイルランド リミテッド | COMPOUND, ORGANIC ELECTROLUMINESCENT ELEMENT, MATERIAL FOR ORGANIC ELECTROLUMINESCENT ELEMENT, AND LIGHT EMITTING DEVICE, DISPLAY DEVICE AND LIGHTING DEVICE USING SAME |
| WO2014078568A1 (en) | 2012-11-14 | 2014-05-22 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
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| US4520024A (en) * | 1983-02-11 | 1985-05-28 | Eli Lilly And Company | Method of selectively blocking peripheral vascular serotonergic receptors |
| FR2635104B1 (en) * | 1988-08-03 | 1992-04-30 | Synthelabo | INDOLONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2637591B1 (en) * | 1988-10-11 | 1992-10-23 | Synthelabo | QUINOLEINONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2655988B1 (en) * | 1989-12-20 | 1994-05-20 | Adir Cie | NOVEL DERIVATIVES OF NAPHT-1-YL PIPERAZINE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| IT1251144B (en) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | BENZIMIDAZOLONE DERIVATIVES |
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- 1994-02-15 EP EP94911377A patent/EP0689536B1/en not_active Expired - Lifetime
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Also Published As
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| CA2158457A1 (en) | 1994-09-29 |
| AU6391894A (en) | 1994-10-11 |
| JPH08503228A (en) | 1996-04-09 |
| FI941213A (en) | 1994-09-17 |
| FI941213A0 (en) | 1994-03-15 |
| HU9400760D0 (en) | 1994-06-28 |
| GR3036394T3 (en) | 2001-11-30 |
| ZA941806B (en) | 1995-09-15 |
| DK0689536T3 (en) | 2001-07-30 |
| EP0689536A1 (en) | 1996-01-03 |
| DE69427289D1 (en) | 2001-06-28 |
| DE69427289T2 (en) | 2001-09-06 |
| WO1994021619A1 (en) | 1994-09-29 |
| PT689536E (en) | 2001-11-30 |
| HUT67312A (en) | 1995-03-28 |
| EP0689536B1 (en) | 2001-05-23 |
| IL108923A0 (en) | 1994-06-24 |
| JP2810236B2 (en) | 1998-10-15 |
| ES2157256T3 (en) | 2001-08-16 |
| ATE201403T1 (en) | 2001-06-15 |
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